Dr. Henry K. Beecher: The Placebo Effect

Your mind can be a powerful drug, but when (if ever) is it ethical to choose mind over matter? Aarati tells the story of an army doctor who observed the placebo effect in soldiers and then went on to transform how we conduct clinical trials. 

Transcript

Aarati Asundi (00:12)
Hi, everyone, and welcome back to the Smart Tea Podcast, where we talk about the lives of scientists and innovators who shape the world. I'm Aarati.

Jyoti Asundi (00:21)
And I'm her mom, Jyoti

Aarati Asundi (00:22)
Today, Mom, I have a kind of different story for you. So normally on this podcast, we talk about scientists who have made breakthroughs in science. But today, I have a story of a scientist who made a breakthrough in the way we do science. So it's a little bit different.

Jyoti Asundi (00:42)
The method rather than the actual result.

Aarati Asundi (00:46)
Mm-hmm, exactly. And so I'm very curious to hear your thoughts on this episode because you are a scientist. You actively do bench science. And so I feel like a lot of what I'm going to talk about today is something that you will have very firsthand knowledge of and will experience all the time. 

Jyoti Asundi (01:06)
This sounds fun yes. I would love to listen to this story.

Aarati Asundi (01:09)
Awesome. So today we are going to be talking about a man named Henry Beecher. He is most known for two things. First is studying the placebo effect.

Jyoti Asundi (01:21)
Yes, placebo. So you're going to talk about clinical trials because sometimes what happens is just because people are getting drugs, they think "Oh, so I should be getting better because the doctor gave me this drug to make me better and the mental fortitude that they get due to being administered a drug that allows them to self heal. And that's like a placebo effect just because you think you should get better you actually do get better. There is self healing. We humans are remarkable organisms.

Aarati Asundi (01:56)
Yeah, mind over matter.

Jyoti Asundi (01:56)
We have remarkable capacity for self-healing.

Aarati Asundi (02:00)
Yeah, so the placebo effect has always been interesting to me. And so that's kind of how I got into this story. But then the second part of his story, he gets really into bioethics. And so we're going to be talking about how we do science ethically and human research ⁓ and the regulations around human experimentation.

Jyoti Asundi (02:21)
This is something that I'm conflicted about even right now. I mean, all the time in my work I have this. And if you marry the two concepts together, the placebo effect and the bioethics, that opens up such a big can of worms.
 
Aarati Asundi (02:36)
Yes, and we're getting into that can of worms today.

Jyoti Asundi (02:39)
Okay.

Aarati Asundi (02:40)
So let's start Beecher's personal story and his life and how he grew up. So Henry was born on February 4, 1904 in Wichita, Kansas to Henry and Mary Unangst. When he was born, he was actually given the name Harry Knowles Unangst. He ended up changing his name to Henry Knowles Beecher later, and we'll get into that. But for now, I'm going to call him Harry. For his childhood, he was known as Harry.

Jyoti Asundi (03:10)
Okay.

Aarati Asundi (03:11)
He was the second of three children, although his older brother Eugene died in infancy. However, his younger sister Ruth survived, and there was about a 10-year age gap between them. The family lived about 20 miles south of Wichita in a small rural town called Peck. And their family did well enough. And Harry had what sounded like a very typical country upbringing for the times. Both sides of his family had settled in the area, so he was surrounded by cousins and grandparents and extended family all the time. The family had a farm that generated some income, but it wasn't anything like extravagant.

Jyoti Asundi (03:51)
But it still sounds like a very idyllic childhood. I can imagine him running around the farm. I always imagine growing up on a farm to be fairly idyllic because you're so close to nature. So what you can learn by actually getting your hands dirty in the soil looking at plants, all of that, you cannot get that from any book or any kind of university.

Aarati Asundi (04:16)
Yeah and he got along with pretty much everyone except for his father. His father, when I was reading about him, of seemed like this quote unquote macho guy. He liked to drink and gamble, and he thought that boys should play sports. And Harry, on the other hand, was more quiet and had more of a gentle nature. He preferred to  read rather than go outside and play with all the other kids. He liked to play the piano. He had a pet parrot for a while, and he liked to garden and bake and make candy. And so I can just see father's like, you're not a real boy. You're not a real man. Like, what is this? 

Jyoti Asundi (04:59)
Yeah, it's, that toxic masculinity. There are people who have a very toxic idea of what masculine should look like. And that's these concepts came out like, boys don't cry or something like that. So then the only outlet for them then becomes anger. And so that leads to so much toxicity and violence. SO I'm glad people are waking understanding that there are definitions of masculinity and what exactly is masculine. So it sounds the son actually is a real man. The father was just a blustering chest-thumping rooster.

Aarati Asundi (05:37)
Yes. And so caused a lot tension between the two of them. 

Jyoti Asundi (05:43)
I can understand.

Aarati Asundi (05:45)
Yeah. After graduating from Wichita High School, Harry enrolled in the University of Kansas. And by this time, the tension between Harry and his father had gotten worse. His father refused to help him financially with university expenses. And so Harry had to work and get loans to put himself through school. And we know that on his registration card for school, Harry listed only his mother as his parent.

Jyoti Asundi (06:09)
Okay.

Aarati Asundi (06:10)
When he entered college, he didn't particularly know what he wanted to do. But by the end of sophomore year, he found himself being drawn to chemistry. He joined the Alpha Chi Sigma fraternity, which is for chemical sciences. He also worked for a summer in a bacteriology lab under Professor Lee E. Treese. in four years, he graduated with his bachelor's of arts in chemistry.
After he graduated, he stayed at the University of Kansas, and he did his master's in physical chemistry. That same year, sadly, in 1927, Harry's mother died of pneumonia.

Jyoti Asundi (06:47)
Oh no!

Aarati Asundi (06:48)
Harry was devastated at the news because his mother was his one true parent.

Jyoti Asundi (06:53)
Yeah, so mentally actually even though he still has his father, he feels orphaned.

Aarati Asundi (06:59)
Yeah. And his little sister, Ruth, was only 13 at the time. And Harry did not trust his father to look after her properly.

Jyoti Asundi (07:09)
Absolutely.

Aarati Asundi (07:11)
And so Harry sued to be her guardian.

Jyoti Asundi (07:13)
Good for him.

Aarati Asundi (07:15)
Yeah. He won the petition along with her inheritance. But, you know, he's this 23 year old guy still trying to go to school. And now he's got this 13 year girl to take care of. And so sure he was very stressed.

Jyoti Asundi (07:30)
But this is a true man actually.

Aarati Asundi (07:33)
Yes, yes.

Jyoti Asundi (07:34)
Unlike the father. This is so funny, isn't it? That the father is looking down upon him for a piano player and a gentle soul. But he is the one who has the guts and determination to make sure that his little sister is done right by. 

Aarati Asundi (07:51)
Yeah, he's shouldering the responsibility of taking care of his family.

Jyoti Asundi (07:55)
Like a real man.

Aarati Asundi (07:56)
Yeah. Ruth knew deep down that Harry loved her, but there were times that he could be a bit harsh. For example, he sold off a little desk that she loved and kind of just told her, get over it, because they needed the money. 

Jyoti Asundi (08:12)
Very sad.

Aarati Asundi (08:13)
But in reading about it, I was reminded of the saying I've seen on social media. A lot of times people will say this, especially about New Yorkers, that New Yorkers are not nice, but they are kind. And I think that really is a very apt description for him, that he was rough around the edges, a bit harsh, but he's doing what's best for you.

Jyoti Asundi (08:37)
It's also, I think that he was absolutely trying to survive at that point. And every decision like this is made through the lens of what's for the greater good. And yes, right now she loves the desk, but there'll be no food on the table if we don't sell the desk. And later we can buy her another desk that she likes. But right now we need food. That kind of practicality, forces you to make extremely harsh and practical decisions. And yes, the other person does feel bad. But what can you do? What can you do? 

Aarati Asundi (09:11)
What can you do? Yeah. But it's just he didn't have that kind of soothing nature. He wasn't very kind about it. He was just like, you need to get over this because we need to do this. And so his bedside manner wasn't great. Yeah.

Jyoti Asundi (09:22)
that's exactly how my dad was. That's exactly how my dad was actually. He would just lay down the law and just say, this is what we need to do. Because he had so much responsibility on his shoulders at such a young age and he brought us up in... basically we were clawing at the edges of poverty and we somehow made our way up. And he would just lay down the law and say, this is what needs to be done. Sorry, can't afford singing lessons even though you like them. No, this is what we're going to do. You're going to do this, that kind of thing. So very, very practical things like that. Yeah.

Aarati Asundi (09:59)
Yeah, I got that same impression from him that, we don't have time for emotions right now. We're just trying to survive. We're just trying to get through this.
So he's just graduated with his BA in chemistry. And a friend from his university helped him get a position as a chemistry teacher at Highland College. In the 1928 yearbook for Highland College, his picture is in there. And it has the caption that says, "Perhaps he'll get to lunch on time and perhaps he won't. But he's at chemistry at 8 o'clock sharp every morning. He is certainly right there with the scientific facts and his grade book. The boarding club is deeply indebted to Mr. Unangst for keeping the mice from the piano and for the musical entertainment, he has furnished them." 

Jyoti Asundi (10:46)
Known for having his priorities smack on. I'm a chemistry teacher and that's what I'm going to be focusing on. And if I miss lunch, well, too bad, isn't it? 

Aarati Asundi (10:57)
So I thought that was a nice little snapshot of him.

Jyoti Asundi (10:59)
Absolutely.

Aarati Asundi (11:01)
Meanwhile, though, Harry was still hoping to continue his education. He wanted to do his PhD in chemistry, but for some reason, his friends and professors back at the University of Kansas were strongly pushing him to go to medical school. They finally persuaded him that, for whatever reason, it was a better course for his life. So while he's teaching at Highland, he's also making sure he has all the prerequisites he needs to apply for Harvard Medical School. I'm not sure why he wanted to go to Harvard specifically, but it could just be it's Harvard.

Jyoti Asundi (11:37)
Yeah, of course. And also it seems to me that people around him really saw him as a shining star with very high potential. And it is likely that it is not just that they said, not only do you need to be in medical school, you need to be at the best medical school because that's your caliber.

Aarati Asundi (11:56)
But I think it was surprising to me that he did end up applying to medical school, because even in his application to Harvard in 1928, he doesn't actually show any interest in medicine or treating patients. Instead, he writes about his research at the University of Kansas and said, "Out of this research experience and past courses has grown the desire to do work in biology, especially bacteriology. In order to fit myself for such research, I hope to get the degree of Doctor of Medicine."

Jyoti Asundi (12:32)
So he's indicating even then that he really wants to pursue a research path.

Aarati Asundi (12:37)
Yes. And so I think today, if you were saying things like that, people would say, why don't you get your PhD then? Because that's what the PhD is for.

Jyoti Asundi (12:45)
Or you know MD PhD maybe. I don't know. Yeah.

Aarati Asundi (12:49)
Yeah, you could do both. But anyway, Harvard was apparently like, good enough for us. You're in. In the summer of 1928, kind of in a final screw you to his father, he officially changed his Harry Knowles Unangst to Harry Knowles Beecher.

Jyoti Asundi (13:09)
And was Beecher his mother's name or something?

Aarati Asundi (13:12)
No, so that's interesting. The Beecher name apparently was somewhere in his family lineage, like his mother's great grandmother's maiden name or something like that. But also, now that he's going to Harvard and he's going to Boston, he's going to be surrounded by all these high society city people. And so the name Beecher, especially in Boston, was associated with a prominent clergyman and abolitionist, Henry Ward Beecher, and his sister, the author, Harriet Beecher Stowe.

Jyoti Asundi (13:47)
Yes, famous. 

Aarati Asundi (13:49)
Yes. And so although he was in no way related, he might have wanted that kind of association.

Jyoti Asundi (13:57)
Yes, He's a small town boy going into big city leagues. He's at least trying to help himself a little bit by having his name not stand out so much. Or if it stands out, it stands out for a good reason. People say, are you related to that good Beecher there? And then "No but yeah, but I like him" or something.

Aarati Asundi (14:17)
I thought it was kind of like changing your last name to Kennedy. Because there's so many people with the last name Kennedy, but does that mean you're related to the Kennedys? 

Jyoti Asundi (14:28)
To the Kennedy family, correct. That's right.

Aarati Asundi (14:30)
Maybe not. But it's hard to prove that you're not. So it just sounds better in social circles that you know.

Jyoti Asundi (14:36)
Yeah, yeah. That makes sense. Yeah.

Aarati Asundi (14:39)
For the same reason, over time, he adopted the first name Henry as well, which was a little bit surprising to me given that that's his father's name and how much he disliked his father. But to him, Harry just sounded more casual and endearing, whereas Henry was someone that you took seriously as a professional.

Jyoti Asundi (14:58)
With some weight. Yeah, yeah. And especially for a medical profession, you want to be like that. Yes.

Aarati Asundi (15:04)
Yeah. So it all in his own head. I mean, we would have been talking about him regardless of his name because he went on to do great things. But he

Jyoti Asundi (15:12)
But you know, this kind of small changes that you make, they help with self-confidence, which allows you to approach life with a different attitude, You're going out there and asserting and taking up the space that you need to take up.

Aarati Asundi (15:28)
Yeah, so he did it to make himself feel better and I love that for him. So off to Harvard Medical School he goes. His little sister Ruth, by the way, stayed home in Wichita. Although she was still technically a minor, she became extremely independent. And pretty much as soon as she turned 18, she went off to Alaska and got married to an army chaplain there. So she just made her own way in life.

Jyoti Asundi (15:53)
Good for her. The kids had to really grow up fast. After their mom died they just had to be practically functioning like adults.

Aarati Asundi (16:01)
She did it for herself.

Jyoti Asundi (16:04)
Good for her.

Aarati Asundi (16:06)
At Harvard Medical School, Henry started to become interested in respiratory physiology and anesthesiology. So if you remember from our episode on Virginia Apgar, anesthesiology at this time is just starting to come into its own as a medical field.

Jyoti Asundi (16:22)
I remember it used to be a domain predominantly run by nurses and it wasn't considered to be high level skill which is the exact opposite of what it is today. Being an anesthesiologist is actually the challenge in medicine today and getting into that field is very hard. But this is right at the cusp where they are recognizing, wait a second, we can't just put a person out and expect them to wake back up after surgery without thinking things through and seeing the body metabolizes the drug and all of that.

Aarati Asundi (17:02)
Yes, exactly. And so Henry joins this wave of young doctors who are going into anesthesiology.

Jyoti Asundi (17:11)
Awesome.

Aarati Asundi (17:12)
He won three research fellowships during this time, and he did research and published papers on how some people developed breathing problems after abdominal surgery that could lead to other complications like pneumonia or lung collapse, which is why, apparently, it's important to do deep breathing exercises after getting surgery to reduce the risk.
He also studied the causes of pneumonia and how lung infections set in. And his work caught the attention of Dr. Edward Churchill, who was a professor of surgery at Harvard. And he ended up taking Henry under his wing. After graduating from Harvard, Henry went to do two years of surgical training under Dr. Churchill at Massachusetts General Hospital. He also got married to a woman called Margaret Swain in 1934, who was the daughter of an obstetrician. So I'm assuming they met through his work at the hospital. Yeah.

Jyoti Asundi (18:10)
Through work and some work party or something.

Aarati Asundi (18:14)
He then traveled to Copenhagen for a year in 1935 to work with Dr. August Krogh who won the Nobel Prize for his work in understanding how capillaries are regulated and control the exchange of oxygen and carbon dioxide in our blood.

Jyoti Asundi (18:31)
Nice. He is moving in very high circles in terms the scientific findings that's going on.

Aarati Asundi (18:38)
Yes, and fun fact, August Krogh is one of the founders of Novo Nordisk, the pharmaceutical company. Novo Nordisk right now is popular because they produce Ozempic and Wegovy, those GLP-1 drugs. Yeah.

Jyoti Asundi (18:54)
Got it. Alright. Makes sense.

Aarati Asundi (18:57)
But obviously they do a lot ⁓ of other things, of course. They're a big pharmaceutical company.

Jyoti Asundi (19:01)
Of course. Yeah.

Aarati Asundi (19:05)
After his year in Copenhagen, Henry came back to the US and was hired by Dr. Churchhill as an anesthetist in chief at Massachusetts General Hospital and an instructor of anesthesiology at Harvard. At the General Hospital, he founded America's first anesthesiology research lab. And over the next several years, he worked to grow it. By 1941, he became a professor of anesthesiology at Harvard, which one source pointed out was a bit ironic because he had never actually trained under an anesthesiologist.

Jyoti Asundi (19:39)
Yeah, but he is able to just pick up the skills enough to actually be a full-time professor of the subject. Amazing.

Aarati Asundi (19:48)
And I mean, also, well, it also goes to show you the times because there probably weren't that many anesthesiologists that he could even study under because it was such a new field.

Jyoti Asundi (19:56)
That's true, it is an emerging field, it is a very very new field. So you kind of pick it up just on the go and then they figure out who is skilled enough to become the teacher for the next generation. That's right.

Aarati Asundi (20:09)
This carries us right into World War II. 

Jyoti Asundi (20:13)
Yeah.

Aarati Asundi (20:14)
The thing that comes in and affects everybody in our stories. 

Jyoti Asundi (20:17)
Everybody, yes.

Aarati Asundi (20:20)
As an anesthesiologist and a researcher, Henry joins the effort as an Army Medical Corps major to study anesthesia in wounded soldiers on the battlefield. He was briefly sent to North Africa and then to Italy. And he's treating wounded soldiers with morphine to relieve their pain. And here's where he makes the first very important observation of his career. So exactly how he makes his observation is up to some debate. Some people say that one day he ran out of morphine. And so instead, he starts giving the wounded soldiers injections of saline just to appease them.

Jyoti Asundi (21:00)
Yes, this is what I was talking- this is where the placebo effect comes in. Yes, yes.

Aarati Asundi (21:05)
Mm-hmm. Yes. So there's no formal mention of this story anywhere. It's kind of a tall tale. But what we do have is a paper that Henry published in 1946, just after the war, called Pain in Men Wounded in Battle. In this paper, he writes about 215 severely wounded soldiers. For each of these soldiers, he asked them, are you in pain? And if they said yes, he asked them to rate it as slight, moderate, or bad. He then asked if they wanted pain relief medication. Surprisingly, about 75 % of the soldiers said that they had either no pain, slight pain, or moderate pain and declined pain medication even when it was offered to them.

Jyoti Asundi (21:53)
Oh that's interesting. Okay.

Aarati Asundi (21:54)
And remember, these are soldiers who are severely wounded.

Jyoti Asundi (21:57)
Yes, yes!

Aarati Asundi (21:59)
And then even the soldiers who accepted pain medication often reported that they were still pain free several hours after he gave them just a small dose of morphine. On the other hand, he's comparing this to cases that he had seen before the war, where people were similarly severely injured in accidents. And he was like, most of those people would rate their pain as really bad and want pain medication. So why is there this difference between soldiers and normal civilians?

Jyoti Asundi (22:31)
Is it the mental fortitude that a soldier has for his profession?

Aarati Asundi (22:35)
Not fortitude, but in his paper, he wrote, "It is important to consider the position of the soldier. His wound suddenly releases him from an exceedingly dangerous environment, one filled with fatigue, discomfort, anxiety, fear, and the real danger of death, and gives him a ticket of safety of the hospital. His troubles are about over, or he thinks they are."

Jyoti Asundi (23:02)
That's a very good point. Yeah, it hurts but it's better than the danger of suddenly being shot on the battlefield. That makes a lot of sense.

Aarati Asundi (23:13)
They're actually relieved to be wounded badly because they're like, this gets me out of the battlefield. Whereas if you're a regular civilian going about your day and you get into some horrible accident, now your life is in disaster mode.

Jyoti Asundi (23:28)
Absolutely. Yeah!

Aarati Asundi (23:31)
And so this gets Henry thinking about the placebo effect, the fact that these soldiers have this intense relief that's somehow able to override their pain.

Jyoti Asundi (23:42)
Yes!

Aarati Asundi (23:43)
And so we knew about the placebo effect at this time. It's an ancient observation. Healers and doctors have recognized for centuries that sometimes convincing a patient that they were helping them just by giving them a sugar pill or even just offering words of comfort could go a really long way towards helping the patient.

Jyoti Asundi (24:04)
Absolutely. This is actually very true. In India I have seen this all the time I was a young girl in India during a time when the GP would actually visit the house. So the doctor actually came with his little black bag to the house of the patient. There would be somebody who would be moaning and groaning and the doctor would just offer sugar pills and that itself would make the person feel so much better. And sometimes it almost feels like the person just wanted some social interaction and put up a fuss until somebody came to visit them.

Aarati Asundi (24:39)
And now it's like, OK, I saw the doctor. Everything's good now. The doctor said I'll be OK. Yeah.

Jyoti Asundi (24:41)
Yes, everything is good. The doctor knows, the doctor looked at me and has offered me these pills which are actually just sugar but I don't know that and I'll be better.

Aarati Asundi (24:52)
The word placebo comes from the Latin phrase meaning "I shall please." And the term "placebo" was formally introduced to medicine in the 1700s by an English physician, Alexander Sutherland, and a Scottish physician, William Cullen. In 1799, a British doctor, John Haygarth, conducted the first real placebo trial. At the time, apparently there were these long metal needle type things called Perkins tractors that were being sold to patients with the claim that they could be used to draw out diseases.

Jyoti Asundi (25:28)
I am glad I don't live in those times.

Aarati Asundi (25:30)
I know, right? Here's a big needle you can stick yourself with. It'll pull out your...

Jyoti Asundi (25:35)
And you can just pull it out and then the disease comes right out. Wow!

Aarati Asundi (25:39)
Yep. They were extremely expensive. And John Haygarth was like, I think you're extorting sick people by calling this needle special somehow when I bet a wooden needle would work just as well. And it did. If he took a wooden needle, a wooden Perkins tractor, and convinced the patient that he was going to be able to draw out their disease with this cheap wooden stick, essentially, the efficacy rate was just as good as using a metal needle,

Jyoti Asundi (26:11)
Because really, both of them are just placebo effects. 

Aarati Asundi (26:15)
Exactly.

Jyoti Asundi (26:15)
Actually, I know he's trying to prove the wooden needle to be the placebo, but in reality now we know you cannot take a needle, stick it in and pull it out. It's all happening mentally. So placebo effect all the way in fact.

Aarati Asundi (26:31)
Mm-hmm, yeah. And so the placebo effect is a known thing. But when Henry makes this observation in soldiers, he takes it a step further. He suggests that maybe doctors should be aware of the placebo effect when it came to treating pain, and therefore use a bit more discretion when handing out drugs like morphine. Because morphine can be dangerous. You can overdose on morphine. 

Jyoti Asundi (26:57)
Yes, and can be highly addictive also.

Aarati Asundi (27:00)
Yeah, and doctors at the time are just giving morphine to people who were in accidents and were maybe just shaken up or confused or in shock. And they weren't clearly articulating that they were in pain.

Jyoti Asundi (27:14)
Correct. You need dose those with a little bit of a light hand.

Aarati Asundi (27:18)
Yes, exactly. So Henry's like, even if the patient is injured, they may not actually be in pain because they're in shock, in which case maybe hold off on giving them morphine or at least start them with a lower dose because not actually in pain. Even if they have this like huge thing, this huge wound, and you're like, you must be in pain, they might be in shock and not be feeling pain. So don't need to treat them for pain. So don't give them something.

Jyoti Asundi (27:43)
That's right. Makes very good sense, absolutely.

_______________________________________________________________________________________

Aarati Asundi (27:55)
Hi everyone, Aarati here. I hope you're enjoying the podcast. If so, and you wish someone would tell your science story, I founded a science communications company called Sykom, that's S-Y-K-O-M, that can help. Sykom blends creativity with scientific accuracy to create all types of science, communications, content, including explainer videos, slide presentations, science, writing, and more. We work with academic researchers, tech companies, nonprofits, or really any scientists. To help simplify your science, check us out at sykommer.com. That's S-Y-K-O-M-M-E-R.com. Back to the story.
_______________________________________________________________________________________


Aarati Asundi (28:41)
So after the war, Henry returned to his anesthesiology lab at Massachusetts General Hospital, and he began to study the placebo effect more carefully. want to preface this by saying that these studies that he was doing were extremely flawed by today's standards. But the main point still remains. He conducted his own small scale experiments, but he also reviewed 15 clinical trials that had been published where patients were given medications for different illnesses, like coughs or anxiety a lot of them were for pain. And in each of these trials, the patients had been split into two groups. One was given the real medication, and the other was given a placebo. And Henry noted that across these 15 trials, about 35 % of the patients who were given a placebo improved.
In 1955, he published this in a paper called The Powerful Placebo. And he argued that doctors had to be more careful when saying how effective a new medicine was because many patients in the placebo group had also gotten better.

Jyoti Asundi (29:45)
Yes. In today's world, the efficacy of the drug has to be percentage above the placebo in order to actually make the cut.

Aarati Asundi (29:55)
Yes. And so that tells you the state of statistics in research at the time also.

Jyoti Asundi (30:01)
Absolutely. The fact that they were actually dividing the patient population into two groups and having a placebo group and a drug group and yet they are not fully analyzing what's happening to the placebos and just saying, yeah, the drug works. That itself says that they haven't completely understood what they're doing. The whole point of the placebo is to see how much better is the drug compared to the placebo group. So yeah placebo, was like one third of the people got better on their own. However, with the 60% of the people got better. And that means there was a drug effect.

Aarati Asundi (30:41)
Yes, yes. 

Jyoti Asundi (30:42)
You have to do that. You have to do that whole statistical comparison.

Aarati Asundi (30:44)
Yeah, you have to do the statistics between the two. Yeah.

Jyoti Asundi (30:46)
Correct. There has to be a distinct difference between the two groups. And if there is, then you don't need to have a third group who is not treated at all. Because you are subtracting self-healing from both.

Aarati Asundi (31:01)
Gotcha. Makes sense. The other thing that we have to note about his studies at this time was that most of the data and the trials that Henry reviewed were very subjective. They were treating patients for anxiety or pain, where you ask the patient how they're feeling before and after giving them the medication.

Jyoti Asundi (31:20)
There is no scale to measure all that. So whatever the patient says, and like you pointed civilian could be saying, "I'm in severe pain" with just a stubbed toe, whereas the soldier is gritting through major injury and saying, "Not really, I'm good. Don't worry about me."

Aarati Asundi (31:40)
Yeah, so there's nothing like quantitative that they're measuring.

Jyoti Asundi (31:43)
Exactly. How are you going to measure that? How are you going to compare the two?

Aarati Asundi (31:47)
Yes. But still, a very important paper, and the impact of this paper on the medical community was interesting. Overall, Henry's paper was the first real push for scientists to start including randomized control groups into clinical trials and to be more rigorous about proving that a new medication actually worked. But in some people's view, it legitimized giving patients placebos instead of medication in certain cases. And that's where we start to veer into the field of ethics. 

Jyoti Asundi (32:22)
I see. 

Aarati Asundi (32:22)
So doctors started to question whether it was ever OK for a doctor to try and fool a patient into thinking that they were getting real medication in hopes of triggering the placebo effect. Or was it always the doctor's job to be honest, even if it meant the patient would not feel confident in their outcome and therefore have a worse outcome because they were feeling bad.

Jyoti Asundi (32:47)
That question is addressed in today's clinical trial where you are evaluating a drug against a placebo. When people sign on to a new clinical trial for a new drug, they are told right off the bat that it's a randomized trial.

Aarati Asundi (33:04)
Yes.

Jyoti Asundi (33:04)
And the person administering it does not have a clue whether it's drug or placebo. So not only does the person receiving the drug versus placebo have no clue, but the person administering it, the doctor also does not know. 

Aarati Asundi (33:19)
That's what they mean by double blind, right? Both are blind.

Jyoti Asundi (33:21)
Double blind. Correct. Some other person, a clinician will prepare the vials to be that need to be administered and just label them something random like A, B, C, D, E, F, G or something and will be other people who never come in touch with the doctor, who never come in touch with the subject and they know what is A and what is B and what is C and what is D so the person who is preparing those vials doesn't know who is going to get it. And the person who receives the vial doesn't know what's in it.

Aarati Asundi (33:54)
Yes.

Jyoti Asundi (33:55)
And then finally after you see the results, then you go back and say, so what was this? 

Aarati Asundi (34:01)
Yes. What did A correspond to? Was A medication or was A placebo? Was B medication or was B placebo? Yeah

Jyoti Asundi (34:05)
Correct. Correct, and that is how you then determine whether there was a drug effect versus the placebo.

Aarati Asundi (34:14)
Yes, so we're starting to think about these questions because back then they weren't doing that at all, you know?

Jyoti Asundi (34:21)
Yes.

Aarati Asundi (34:21)
And these questions just added to other ethical questions that had arisen from Henry's work. For example, if a patient couldn't articulate fully what they were feeling, maybe because the situation they were in was so traumatic, was it more ethical to withhold pain treatment because the patient couldn't consent, or was it more ethical to give it to them? And more recently, it came out in July 2007, so many years after Henry's death, that after World War II, Henry had actually continued to consult with the US government on anesthesia and its potential use as a mind-altering drug.

Jyoti Asundi (35:02)
Oh I see. 

Aarati Asundi (35:05)
So in the 1950s, the CIA was conducting a series of highly classified projects under the code name MK Ultra, which maybe you remember Arpita talked about this a little bit in her episode on Albert Hoffman and LSD. ⁓ This was a couple of years ago that we did that episode. But.

Jyoti Asundi (35:25)
Yes.

Aarati Asundi (35:26)
But basically, MKUltra were highly unethical experiments on people that used a combination of mind-altering drugs like LSD and anesthesia, That's why they brought Henry in. And they combined that with torturous interrogation techniques to see if they could develop a kind of truth serum for identifying spies and double agents.

Jyoti Asundi (35:51)
Hard. That is rough to listen to. Okay.

Aarati Asundi (35:55)
Yes. And we think that Henry saw many of the atrocious violations of human rights during his involvement in this project. And this is what prompted him to become an advocate for ethical medical research.

Jyoti Asundi (36:09)
Ah that a lot of sense. 

Aarati Asundi (36:12)
Yes. It's also important to note that there were rules to protect human rights in scientific experimentation that had been established by the Nuremberg Codes in 1947, following World War II. And then in 1953, the NIH created a policy that required informed consent from volunteers. But oftentimes, American researchers would ignore these rules and even outright argue against them. So Henry was not outright accusing American researchers of this, but he was strongly drawing the comparison saying that if Americans were breaking the Nuremberg codes, we're no better than the Nazis.

Jyoti Asundi (36:52)
Absolutely. Yes, we saw the horrors inflicted upon ordinary people by that regime. Yes, so we do need to have those kind of ethics in place. 

Aarati Asundi (37:02)
Yes, and you need to follow them because otherwise...

Jyoti Asundi (37:03)
And they need to be followed. 

Aarati Asundi (37:04)
Yeah, what's the point? You can't say these rules are for the Nazis and not for us.

Jyoti Asundi (37:09)
Yeah. Correct. Correct. Because then you're no better. Yeah.

Aarati Asundi (37:14)
In 1965, the Upjohn Pharmaceutical Company held a conference in Kalamazoo, Michigan, and they asked Henry to come talk about medical ethics. Henry prepared a 40-minute speech in which he basically dropped this massive bombshell citing at least 18 published studies, which he said violated basic human rights.

Jyoti Asundi (37:36)
No way.

Aarati Asundi (37:37)
Yes. His speech was not well received.

Jyoti Asundi (37:41)
Of course.

Aarati Asundi (37:41)
Medical investigators criticized him, saying he was exaggerating and making irresponsible allegations. But this only encouraged Henry to go one step further. The following year in 1966, he basically took his speech and turned it into a paper called Ethics and Clinical Research. In it, he described 22 clinical trials where patients had been exposed to something risky or harmful without their consent and sometimes without even knowing that they were part of an experiment. 

Jyoti Asundi (38:11)
No way! wow! Wow! That is so scary!

Aarati Asundi (38:15)
I know, right? Can you imagine?

Jyoti Asundi (38:17)
You go to the doctor for something and all of a sudden you are inadvertently made into a guinea pig for something that- some other agenda that's going on in the background that you have no awareness of.

Aarati Asundi (38:32)
Yeah. He didn't name any names of researchers or universities, but the paper was still rejected by the Journal of the American Medical Association for being too controversial.

Jyoti Asundi (38:42)
Yeah, they didn't want the inflammatory information to be out there because people basically will lose trust in doctors then.

Aarati Asundi (38:50)
Yes. And also I think it was like, even though he didn't name many names in many cases, it was pretty obvious. 

Jyoti Asundi (38:58)
You know. When you know, you know. That kind of thing. So when you are in the inner circle, you know exactly what. Because, If he's citing 22 clinical trials, people who are in the business know ran them.

Aarati Asundi (39:13)
Yes, exactly.

Jyoti Asundi (39:13)
 Yeah, the ordinary man on the street may not know that. But the people who are in the know, they know is doing this. And probably people with big names and big money as well and so they have again they have the- you know, money talks and they have the ability to suppress this kind of information.

Aarati Asundi (39:32)
Yeah. But it was published by the New England Journal of Medicine after the editor-in-chief overruled six out of seven peer reviewers who had also wanted to reject it.

Jyoti Asundi (39:43)
Wow, that's I- He found an ally.

Aarati Asundi (39:47)
Yes.

Jyoti Asundi (39:48)
You know what this reminds me of? It reminds me of 12 Angry Men, the movie. 

Aarati Asundi (39:53)
Oh yeah!

Jyoti Asundi (39:54)
Yeah. In that there is one guy who is like let's at least give this a fair trial. And if all 11 of you reject it, then I'll wind up. But then he finds one ally and then finally at the end of the movie he is able to completely exonerate the young boy on trial. This is what it reminds me of. You need one ally when you fight these kind of lonely for justice.

Aarati Asundi (40:18)
Yes. So this paper gets published, and people are reading it. And in some of the trials that he described, scientists are doing truly unethical things. In one trial, scientists had given patients an injection that they said contained, "some cells". And they conveniently left out the fact that they were live cancer cells.

Jyoti Asundi (40:43)
No! 

Aarati Asundi (40:44)
Yeah. 

Jyoti Asundi (40:45)
You go to a doctor and you get injected with live cancer cells?

Aarati Asundi (40:49)
Without your knowledge or consent or knowing anything about it.

Jyoti Asundi (40:52)
That is shocking. That is absolutely shocking. And that should be classified as murder. 

Aarati Asundi (41:00)
Or attempted murder. Yeah

Jyoti Asundi (41:02)
Yeah, that's attempted murder. And if the person dies, it is murder.

Aarati Asundi (41:05)
Yeah. Just crazy. In another case, patients with a bacterial infection were not given antibiotics because researchers wanted to see how the disease progressed naturally and compare it to their drug, even though there was an effective antibiotic that existed.

Jyoti Asundi (41:24)
This is so difficult to listen to.

Aarati Asundi (41:26)
Yeah, well, I was wondering like today if you were, testing a new drug and there was already a drug that existed, but you wanted to know if your drug was better. Wouldn't your control group get the existing drug and you would compare your drug to it?

Jyoti Asundi (41:43)
They do- yeah so they things like that where they'll have, six or seven randomized arms like multiple companies are targeting the same indication with similar drugs. Then you have a big platform and each arm in the trial is given one of the drugs and then there is a placebo also and everything is double-blinded and then you open it all and say who did best. 

Aarati Asundi (42:06)
And I wonder also if in this particular case they could have done it better in terms only take this experiment for two weeks after which time you will get whatever antibiotic it is. Like not put your life in danger, basically.

Jyoti Asundi (42:20)
Yes, you're right. That is absolutely right. That's exactly what they do today actually. Open label, that's what they call it. Where if you already know that there is efficacy with the drug then you wait for a month or so or whatever the stipulated time but then when you start to see that the people who getting the drug are seeing the response, at that time everybody realizes, the drug is effective, point number one. The second point is, even though it is supposed to be double blinded, it's no longer blinded because the doctors who are administering it, the nurses who are administering it, the patients if they are talking to each other, everybody sees that fellow is getting better and I'm not or vice versa. The doctor is seeing multiple patients and knows exactly who is getting better and who is not. At which point then again, the ethical question comes and then they say, I cannot in good conscience continue to give the placebo to these people. Give me the drug for everybody.

Aarati Asundi (43:31)
Gotcha. Okay.

Jyoti Asundi (43:31)
So they keep it randomized and closed and double blinded for a certain amount of time and then they open it.

Aarati Asundi (43:37)
Yes. So I think in this case...

Jyoti Asundi (43:40)
...they should have opened it up after a certain amount of time.

Aarati Asundi (43:43)
Yeah, and I think what made it even worse is that a lot of these patients were not able to consent properly, either because they were handicapped in some way, or they were minors, or they were coerced by the researchers into believing that they couldn't say no to taking part in the experiment. 

Jyoti Asundi (44:03)
Terrible, terrible. 

Aarati Asundi (44:05)
Of course, this paper sparked immediate public outcry. People were shocked and outraged that medical professionals would ignore such basic human rights. There was a lot of back and forthing with some clinicians trying to undermine Henry's paper or say that the claims were exaggerated. And many that he was just trying to get his 15 minutes of fame by pointing fingers. But eventually the government was forced to act. 
It took a while though. So it wasn't until 1972, which is like seven or eight years later, that a lawyer named Peter Buxtun blew the whistle on an unethical study that involved 400 African-American people in Tuskegee, Alabama, who had syphilis and went into a study thinking that they would be getting free health care when in fact researchers withheld giving them penicillin, which was a well-established treatment for syphilis.

Jyoti Asundi (45:02)
Wow! That's so wrong.

Aarati Asundi (45:05)
When the news broke, a group called the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was formed. And they established guides for human research. And finally, in 1981, the government passed a law requiring that experiments involving human subjects needed to have informed consent and that trials needed to be approved by institutional review boards, or IRBs.

Jyoti Asundi (45:33)
Ah! The IRB, that's when the IRB came into play. Okay, yeah, we have to write long, long, long pieces to the IRB when something needs to get through there, yes.

Aarati Asundi (45:44)
Just for people who don't know, an IRB is a panel of researchers that is in a similar field but not directly involved in the experiment. 

Jyoti Asundi (45:52)
So they have the scientific understanding but they don't have a stake in the game so they are able to make a decision.

Aarati Asundi (46:02)
Mm-hmm, exactly.

Jyoti Asundi (46:03)
Yes, and now the IRBs are in place even for animal studies.

Aarati Asundi (46:07)
Oh, yeah, Arpita was actually telling me about that. I never had to do that because I was working on little tiny worms like proliferate like crazy. They're invertebrates and you know...

Jyoti Asundi (46:19)
Yeah, but if you are working with any of the models mice or rats or any other higher species, you have to have an IRB review ensure that you're not causing unnecessary pain, you're keeping them healthy and as comfortable as you possibly can. So for example if a causing a loss of body weight, that's one of the side effects of the drug there will be a cutoff that you watch this animal starve itself to death. There are cut-offs like okay 10 % body weight loss, 20 % body weight loss and then you go to procedure A, procedure B whatever it is. It's already laid out beforehand.

Aarati Asundi (47:00)
Yeah, So this is where that kind of thing finally came into effect. Henry stayed at Massachusetts General Hospital as chief of anesthesia until 1969. During that time, he established Harvard's first IRB.

Jyoti Asundi (47:17)
So even though the entire world was in uproar due to his publication position at Harvard was still strong and the institution didn't turn against him.

Aarati Asundi (47:29)
Yes, I think that there were individual clinicians or researchers who were like, "Oh my god, he's creating such a pain the butt for us. Now we have all this paperwork we have to do, and all because he's raising this big stink ethics or whatever." And so there were people that were upset with him, even at Harvard or Massachusetts General Hospital. But the world at large, or the government and the public were basically like, no, but he's right, though. You can't do whatever the heck you want and at the expense of human lives and human well-being. And so yes, maybe it's a bit of a pain to have to go through an IRB now when you didn't have to before. But if it means safeguarding, people's health and people's wellbeing, then yeah, it's necessary.
And as if studying the placebo effect and overhauling ethical research wasn't good enough, Henry is also known for one more thing, which is in 1968, he wrote a paper called A Definition of Irreversible Coma, in which he established criteria for when a person was considered brain dead and could therefore ethically be taken off of life support.

Jyoti Asundi (48:45)
Oh! That's a big contribution.

Aarati Asundi (49:48)
Whereas prior to this, death was largely based on whether the heart was still beating or not.

Jyoti Asundi (49:54)
Yeah, and that it's highly subjective. So if the heart continues to beat for 30 years, when the person is actually, you know, not present at all, you're just racking up medical bills and burdening the family.

Aarati Asundi (49:03)
Yeah. There's no life there. And he's the one who laid out these criteria that brain death also equals death.

Jyoti Asundi (49:18)
Yes. Brilliant contribution. That's the big one.

Aarati Asundi (49:22)
Henry died on July 25, 1976, of pancreatic cancer at his home in Boston at the age of 72. Like I said, it only came out after his death that Henry was involved in MKUltra. And people were initially shocked to learn this because he had been living his life as this paragon of human ethics.

Jyoti Asundi (49:46)
Yes.

Aarati Asundi (49:46)
And for him to have been involved in any way in unethical studies was really surprising to a lot of people. But then people afterwards went back and looked at the timing of everything. And they were like, no, this actually makes sense that his involvement is what actually led him to care so much about ethics.

Jyoti Asundi (50:06)
Yes, because he saw how bad it can be firsthand and then he realized, no, there needs to be guardrails around this. 

Aarati Asundi (50:14)
Yes, exactly.

Jyoti Asundi (50:16)
There is just too much power in the hands of these clinicians that they just willingly conduct their own little side experiments without the person even knowing. Literally you're treating human beings like guinea pigs who have no will, no consent, no information, you're sitting in a cage built by the clinician around your mind.

Aarati Asundi (51:39)
Mm-hmm. And so now, thanks to him, we conduct clinical studies much more ethically. Even in my PhD, had to take an entire course on ethics in biomedical research, even though I was working on worms. And I wasn't working with any vertebrate animals. I wasn't working with any human subjects. I wasn't even getting blood from patients or anything. I wasn't even working samples. But I still had to go through this course. And it's a required course for anyone now doing a PhD or an MD. You have to go through an ethics course.

Jyoti Asundi (51:16)
Makes very good sense. We have a lot to be grateful for because he did not put those guardrails in place then once people realize that clinicians are just doing whatever they want, then clinical trials themselves will lose their credibility and their legitimacy. And then making new drugs becomes harder. This whole thing has a boomerang effect. You think you're getting away with a lot of little, little nonsense here and there that person never knew this person never knew kind of thing. But ultimately truth comes and then people just say no we don't believe any of these clinical trials nobody's going to enroll in that. Much rather die at peace at home. But now people still feel yes i can i can help the next person who gets this disease. I may get the placebo, I may get the drug. I don't know, I may live, I may die, but I'll be treated like a human being with dignity. I can go in, enroll, and give these researchers some information. And then next generation... If my kid, if my grandkid gets the same disease due to heredity or whatever, there will be a drug by that time for him. And I'll go in the clinical trial. So that kind of confidence is there, walking into a clinical trial.

Aarati Asundi (52:32)
Yeah. It is also nice every once in a while to just kind of peek behind the curtain and see how much actually goes into creating a drug like Ozempic or Wegovy before it hits the market. There's so much involved, you know? And can take years. It can take decades even for a drug to get...

Jyoti Asundi (52:53)
Yes, and so much structure around it.

Aarati Asundi (52:56)
Mm-hmm. So many people are involved. 

Jyoti Asundi (52:58)
And this is actually a point that I have brought up again, because I'm on the drug development side of things that people do say, "Why the heck does an aspirin, a simple aspirin cost so much?" But this is the reason because everything that finally reaches the patient has been put through a lot of paces and all of that costs money and for the next drug to be made, that money has to be somehow recovered so that then it can be put towards the next drug on the market.

Aarati Asundi (53:30)
Yeah. I was really excited to share this one with you, especially because of your expertise and knowledge in this area. So I'm really glad you enjoyed it.

Jyoti Asundi (53:37)
I would not overstate it to that level: "expertise". I would say some familiarity with the terms is what I am at. THe real experts would laugh at me if I call myself....

Aarati Asundi (53:46)
Well, you're more of an expert than me, so.

Jyoti Asundi (53:49)
I have a little more, a little more information. I'm more familiar with the terms. Let us just put it that way.

Aarati Asundi (53:55)
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