WEBVTT 00:00:21.380 --> 00:00:30.660 MORGAN GRACE: I think I kind of always knew that I had something different than other kids. 00:00:30.660 --> 00:00:33.840 I have danced since I can remember. 00:00:33.840 --> 00:00:36.525 Whenever I hear any kind of music, 00:00:36.525 --> 00:00:38.920 I can't just sit still. 00:00:40.850 --> 00:00:44.470 I loved being on stage. 00:00:46.750 --> 00:00:51.990 It started to like get worse as I was going through puberty. 00:00:52.470 --> 00:00:58.970 But I just remember a wave of pain washed over my body. 00:00:58.970 --> 00:01:02.490 When I go through a bad pain crisis, 00:01:02.490 --> 00:01:05.110 they come out of nowhere. 00:01:06.070 --> 00:01:13.470 I had to quit dancing because of being in the hospital. 00:01:13.620 --> 00:01:19.350 It just made a lot of things in my life have to stop. 00:01:19.730 --> 00:01:22.210 MORGAN'S MOM: Morgan! 00:01:24.980 --> 00:01:28.700 Narrator: Morgan has sickle cell disease, 00:01:28.700 --> 00:01:33.260 an inherited condition that affects her red blood cells. 00:01:34.020 --> 00:01:40.740 Before modern medicine, many people with this disease didn't survive into adulthood. 00:01:41.180 --> 00:01:48.000 The theory of evolution by natural selection predicts that harmful traits should be rare. 00:01:48.000 --> 00:01:53.340 But what's so puzzling about sickle cell is that it's relatively common, 00:01:53.340 --> 00:01:57.740 especially in people with ancestry from certain parts of the world. 00:01:57.740 --> 00:02:03.800 Figuring out why this harmful trait is so common will take us on a remarkable journey 00:02:03.800 --> 00:02:26.050 of scientific discovery. 00:02:26.050 --> 00:02:27.850 NURSE: Dr. Acher will see you. 00:02:31.760 --> 00:02:36.760 DR. NATASHA ARCHER: Hematology is the study of blood disorders. 00:02:37.640 --> 00:02:45.480 A pediatric hematologist takes care of children with those blood disorders. 00:02:45.480 --> 00:02:48.080 Hi. How are you? 00:02:48.080 --> 00:02:48.590 MORGAN GRACE: I'm good. 00:02:48.590 --> 00:02:49.700 DR. ARCHER: You started school already? 00:02:49.700 --> 00:02:51.340 MORGAN GRACE: Yes, I started last week. 00:02:51.340 --> 00:02:53.620 DR. ARCHER: I really got interested in hematology when 00:02:53.620 --> 00:02:57.510 I started to meet patients who had sickle cell disease. 00:02:58.240 --> 00:03:04.280 NARRATOR: Sickle cell disease is caused by a change or mutation in a single gene. 00:03:04.280 --> 00:03:08.640 The gene codes for a subunit of the protein hemoglobin, 00:03:08.640 --> 00:03:12.420 the protein in red blood cells that binds oxygen. 00:03:12.420 --> 00:03:16.060 A mutation in a single nucleotide in the gene 00:03:16.060 --> 00:03:19.960 causes a single amino acid change in each subunit, 00:03:19.960 --> 00:03:23.140 which in turn causes the hemoglobin molecules to 00:03:23.140 --> 00:03:26.745 stick together and change the shape of the red blood cells. 00:03:26.745 --> 00:03:28.780 DR. ARCHER: Typically, red blood cells have 00:03:28.780 --> 00:03:33.615 this disc shape to them that enable them to move throughout the body with ease. 00:03:33.615 --> 00:03:38.465 Sickle cell disease makes the red blood cells a little bit more rigid, 00:03:38.465 --> 00:03:43.550 so changes the shape and makes it like a crescent moon or sickle shape. 00:03:43.550 --> 00:03:48.570 That rigidity of the red blood cell causes them to block blood vessels, 00:03:48.570 --> 00:03:51.550 not allowing blood to get to different parts of the body, 00:03:51.550 --> 00:03:54.290 causing severe and debilitating pain. 00:03:54.290 --> 00:04:00.920 For a pain crisis, my patients typically describe it as a pain that won't go away. 00:04:00.920 --> 00:04:06.265 Thinking of your worst pain and not being able to do anything about it, really. 00:04:06.265 --> 00:04:09.310 You're doing great. Keep up the good work. 00:04:09.310 --> 00:04:11.090 You've taken your medicine, 00:04:11.090 --> 00:04:13.830 and I'll see you in 3 months. 00:04:15.740 --> 00:04:20.160 MORGAN GRACE: In kindergarten, we had this book. 00:04:20.160 --> 00:04:23.170 It's about this young girl with sickle cell, 00:04:23.170 --> 00:04:24.830 but she didn't really know what it was. 00:04:24.830 --> 00:04:28.410 She just ended up in the hospital quite often. 00:04:28.730 --> 00:04:34.010 I could remember having that feeling like I'm in the hospital, 00:04:34.010 --> 00:04:36.330 but I don't really know why. 00:04:40.100 --> 00:04:43.600 It was really just a lot. 00:04:48.980 --> 00:04:52.160 NARRATOR: American researchers first began to study 00:04:52.160 --> 00:04:55.365 sickle cell diseases in the early 20th century. 00:04:55.365 --> 00:05:00.580 DR. ARCHER: In the US, it was most common among individuals of African ancestry. 00:05:00.580 --> 00:05:05.370 They assumed that it was a condition from Africa. 00:05:05.370 --> 00:05:10.060 NARRATOR: But no one could explain why sickle cell would be more common in Africa. 00:05:10.060 --> 00:05:12.760 Then in the early 1950s, 00:05:12.760 --> 00:05:16.340 a Kenyan medical student named Tony Allison made 00:05:16.340 --> 00:05:18.260 a surprising discovery while conducting 00:05:18.260 --> 00:05:21.510 research on different blood type groups in East Africa. 00:05:21.510 --> 00:05:26.570 TONY ALLISON: I actually learned just before going out about the sickle cell condition. 00:05:26.570 --> 00:05:31.075 Nobody really knew the frequencies of sickle cells in East Africa. 00:05:31.075 --> 00:05:35.410 NARRATOR: Allison wanted to measure the frequencies of the sickle cell allele. 00:05:35.410 --> 00:05:39.070 He knew that we inherit 2 copies of most of our genes, 00:05:39.070 --> 00:05:42.310 1 from each of our biological parents. 00:05:42.310 --> 00:05:46.950 These copies called alleles can be the same or different. 00:05:46.950 --> 00:05:52.410 People with 2 copies of the allele without the sickle cell mutation are homozygous, 00:05:52.410 --> 00:05:55.410 which means their alleles are the same. 00:05:55.410 --> 00:05:59.590 They have round red blood cells and they don't have sickle cell disease. 00:05:59.590 --> 00:06:04.670 People with 2 copies of the allele with the mutation are also homozygous, 00:06:04.670 --> 00:06:07.005 but for the sickle cell allele. 00:06:07.005 --> 00:06:11.920 Many of their red blood cells are sickled and they have sickle cell disease. 00:06:11.920 --> 00:06:16.100 People with 1 allele with the sickle cell mutation and 1 allele 00:06:16.100 --> 00:06:22.160 without are heterozygous and have what scientists call sickle cell trait. 00:06:22.160 --> 00:06:25.940 Under most circumstances, their red blood cells 00:06:25.940 --> 00:06:29.920 are round and they don't have any symptoms of the disease. 00:06:29.920 --> 00:06:33.280 At the time Tony Allison did his research, 00:06:33.280 --> 00:06:36.600 there was no genetic test for sickle cell mutation. 00:06:36.600 --> 00:06:40.940 All he could do was look at the blood cells of individuals. 00:06:42.020 --> 00:06:45.470 DR. ARCHER: Tony Allison's major challenge 00:06:45.470 --> 00:06:48.770 was really trying to identify who were the heterozygous. 00:06:48.770 --> 00:06:52.930 It's only in prolonged low oxygen environments 00:06:52.930 --> 00:06:56.140 that their blood cells actually become sickled. 00:06:57.080 --> 00:07:01.530 Here's the blood of a patient with a sickle cell trait. 00:07:01.530 --> 00:07:05.290 They have only 1 sickle cell allele copy. 00:07:05.290 --> 00:07:08.170 If you look at this patient's blood under the microscope, 00:07:08.170 --> 00:07:11.590 it looks completely normal under normal conditions. 00:07:11.590 --> 00:07:14.750 NARRATOR: Researchers can mix a chemical agent to that drop 00:07:14.750 --> 00:07:18.630 of blood which creates a low oxygen environment. 00:07:19.000 --> 00:07:21.280 After a few hours, 00:07:21.280 --> 00:07:24.000 the red blood cells start to sickle. 00:07:24.000 --> 00:07:27.900 This allows researchers to distinguish between someone with 00:07:27.900 --> 00:07:32.720 no sickle cell alleles and someone with sickle cell trait. 00:07:32.720 --> 00:07:35.760 Allison used this simple test to measure 00:07:35.760 --> 00:07:39.785 the frequency of sickle cell traits in some parts of Kenya. 00:07:39.785 --> 00:07:43.515 TONY ALLISON: You could do it in the field, and I did. 00:07:43.515 --> 00:07:51.020 I had a little traveling microscope run off a small bulb that came from a car battery. 00:07:51.020 --> 00:07:54.040 NARRATOR: After analyzing hundreds of samples, 00:07:54.040 --> 00:07:57.200 an interesting geographic pattern started to emerge. 00:07:57.200 --> 00:08:03.140 TONY ALLISON: But what was striking was that you had high frequencies of people carrying 00:08:03.140 --> 00:08:06.440 the sickle cell character in the coast and near 00:08:06.440 --> 00:08:11.560 Lake Victoria and very low frequencies in the high country in between, in Nairobi. 00:08:11.560 --> 00:08:14.730 NARRATOR: In the lowlands, 00:08:14.730 --> 00:08:18.230 the sickle cell trait frequencies were over 20 percent. 00:08:18.230 --> 00:08:19.590 Whereas in the highlands, 00:08:19.590 --> 00:08:22.930 the frequencies were less than 1 percent. 00:08:22.930 --> 00:08:27.770 What could explain such dramatic differences between these regions? 00:08:27.770 --> 00:08:31.610 A childhood memory helped Tony make the connection. 00:08:31.610 --> 00:08:34.130 Allison had caught malaria, 00:08:34.130 --> 00:08:38.930 a deadly infectious disease on a family vacation to the Kenyan coast. 00:08:38.930 --> 00:08:42.430 He knew very well that the humid lowlands around 00:08:42.430 --> 00:08:46.150 Lake Victoria are breeding grounds for the Anopheles mosquito, 00:08:46.150 --> 00:08:49.370 which spread the malaria parasite. 00:08:50.210 --> 00:08:54.050 Allison also knew that these mosquitoes, and 00:08:54.050 --> 00:08:58.010 the malaria they spread, are not common in the drier highlands. 00:08:58.010 --> 00:09:01.960 Could sickle cell and malaria somehow be connected? 00:09:01.960 --> 00:09:05.450 TONY ALLISON: If that's the case, you predict that you have 00:09:05.450 --> 00:09:10.125 high frequencies of sickle cells only in areas where malaria is endemic. 00:09:10.125 --> 00:09:12.190 NARRATOR: To test this hypothesis, 00:09:12.190 --> 00:09:16.190 Allison needed data from more people and a larger area. 00:09:16.190 --> 00:09:19.970 He visited markets and villages throughout Uganda, Kenya, 00:09:19.970 --> 00:09:24.730 and Tanzania, offering checkups and medicine to the people in those markets. 00:09:24.730 --> 00:09:30.130 During these checkups, he collected about 5,000 blood samples. 00:09:30.130 --> 00:09:34.110 The research of Allison and others confirmed that there is 00:09:34.110 --> 00:09:39.485 a strong correlation between the frequency of sickle cell trait and malaria. 00:09:39.485 --> 00:09:43.040 Tony wondered if having a sickle cell allele 00:09:43.040 --> 00:09:47.320 offered an advantage to people living in areas with malaria. 00:09:47.320 --> 00:09:50.395 How could he test this hypothesis? 00:09:50.395 --> 00:09:56.160 TONY ALLISON: You look at malaria in children of the appropriate age and find out whether they are, 00:09:56.160 --> 00:09:58.460 in fact, protected against malaria. 00:09:58.460 --> 00:10:01.700 NARRATOR: He collected blood samples from children aged 00:10:01.700 --> 00:10:06.560 5 months to 5 years and analyzed them under a microscope. 00:10:06.560 --> 00:10:12.115 In each sample, he counted the number of parasites that caused malaria. 00:10:12.115 --> 00:10:15.160 He then compared the parasite counts in 00:10:15.160 --> 00:10:19.290 children with sickle cell trait to those without. 00:10:21.250 --> 00:10:25.950 TONY ALLISON: The sickle cell trait would have lower parasite counts. 00:10:27.070 --> 00:10:31.565 NARRATOR: This was the strongest evidence yet that the sickle cell trait 00:10:31.565 --> 00:10:36.270 gave heterozygotes an advantage where malaria was present. 00:10:38.230 --> 00:10:41.750 People with no sickle cell allele were less 00:10:41.750 --> 00:10:45.660 likely to survive and reproduce due to malaria. 00:10:45.970 --> 00:10:50.090 People with 2 sickle cell alleles were less likely to 00:10:50.090 --> 00:10:54.185 survive and reproduce due to sickle cell disease. 00:10:54.185 --> 00:11:00.185 But people with one sickle cell allele were more likely to survive and reproduce. 00:11:00.185 --> 00:11:06.620 Tony Allison had discovered the first clear example of natural selection in humans, 00:11:06.620 --> 00:11:11.555 but how did the sickle cell allele protect people from malaria? 00:11:11.555 --> 00:11:16.010 TONY ALLISON: I have to say, I left that part of this story to 00:11:16.010 --> 00:11:20.970 others because it's quite a complex story. 00:11:21.700 --> 00:11:28.295 NARRATOR: The parasite that causes malaria feeds on hemoglobin inside red blood cells. 00:11:28.295 --> 00:11:33.230 Natasha Archer studies how the sickle cell trait affects this process. 00:11:33.230 --> 00:11:35.105 DR. ARCHER: When a mosquito bites you, 00:11:35.105 --> 00:11:38.750 the parasite makes its way into the red blood cells. 00:11:38.750 --> 00:11:43.955 Eventually, it releases these proteins that attach to 00:11:43.955 --> 00:11:49.250 blood vessels and force the red blood cell to stay in one location. 00:11:49.250 --> 00:11:53.045 What's unique about the blood vessels that it sticks 00:11:53.045 --> 00:11:57.830 to is that those environments typically have low oxygen. 00:11:57.830 --> 00:12:01.310 If you remember, individuals with sickle cell trait, 00:12:01.310 --> 00:12:06.740 their red blood cells sickle if they are in prolonged low oxygen environments. 00:12:06.740 --> 00:12:13.670 The malaria parasite now will not have hemoglobin that's as easily digestible. 00:12:13.670 --> 00:12:16.400 NARRATOR: Without hemoglobin to feed on, 00:12:16.400 --> 00:12:20.735 malaria parasites can't grow or reproduce as quickly. 00:12:20.735 --> 00:12:25.070 DR. ARCHER: Our research takes us one step further in understanding 00:12:25.070 --> 00:12:30.305 how sickle cell trait is protective against malaria. 00:12:30.305 --> 00:12:35.030 NARRATOR: Malaria occurred in many regions around the world. 00:12:35.030 --> 00:12:43.050 Does the pattern Tony Allison observed in East Africa also occur in these other regions? 00:12:48.970 --> 00:12:54.320 MATHEW GLARUM: What I love about playing music is that when I am up there playing, 00:12:54.320 --> 00:12:56.990 there's nothing but that. That's my therapy. 00:12:56.990 --> 00:13:05.690 'Cause I can’t hold her anymore. Can’t pass the time. 00:13:05.690 --> 00:13:10.670 According to my grandma, I was begging her for guitar lessons at 5-years-old. 00:13:10.670 --> 00:13:14.340 It's always been around in my life, instruments and stuff. 00:13:26.230 --> 00:13:28.565 When I was born, 00:13:28.565 --> 00:13:31.640 my mom knew to look out for us 00:13:31.640 --> 00:13:36.785 potentially having sickle cell because my brother, 00:13:36.785 --> 00:13:39.060 he was born with it. 00:13:41.980 --> 00:13:47.000 When you're a kid and all you want to do is have fun with your friends, 00:13:47.000 --> 00:13:50.790 we could get pain, get taken to the hospital. 00:13:54.610 --> 00:13:58.220 We couldn't participate in holidays, 00:13:58.220 --> 00:14:01.985 family vacations, and we couldn't go to school. 00:14:01.985 --> 00:14:04.310 That gets in the way a little bit. 00:14:04.310 --> 00:14:08.225 Now, as an adult, I've had experiences where my sickle cell 00:14:08.225 --> 00:14:12.870 and getting into a crisis has messed up important stuff. 00:14:13.540 --> 00:14:19.655 My mom's part of the family comes from the Mediterranean area in Sicily. 00:14:19.655 --> 00:14:23.970 Then my dad is from Norway and then Belize. 00:14:24.160 --> 00:14:27.830 DR. ARCHER: When we look at the people who carry the sickle cell allele, 00:14:27.830 --> 00:14:31.820 they share recent ancestry with regions that have historically experienced 00:14:31.820 --> 00:14:36.935 high rates of malaria like sub Saharan Africa, Greece, Italy. 00:14:36.935 --> 00:14:40.265 NARRATOR: Several studies have shown that throughout the world, 00:14:40.265 --> 00:14:44.360 the frequency of the sickle cell allele tends to be lower in areas with 00:14:44.360 --> 00:14:49.055 little to no malaria and higher in areas with a lot of malaria, 00:14:49.055 --> 00:14:53.630 similar to what Tony Allison and other researchers observed in Africa. 00:14:53.630 --> 00:14:57.050 Scientists have observed similar patterns with 00:14:57.050 --> 00:15:01.500 other inherited conditions that affect red blood cells. 00:15:01.630 --> 00:15:05.345 DR. ARCHER: I also treat patients who have mutations in other genes, 00:15:05.345 --> 00:15:07.805 which cause diseases like ovalcytosis, 00:15:07.805 --> 00:15:12.185 Thalassemia, G6PD enzyme deficiency and others. 00:15:12.185 --> 00:15:18.035 NARRATOR: Mutations in these genes also make it harder for the malaria parasite to infect, 00:15:18.035 --> 00:15:22.130 survive, or reproduce in red blood cells. 00:15:22.130 --> 00:15:24.470 DR. ARCHER: Just like the sickle cell allele, 00:15:24.470 --> 00:15:29.825 all of the alleles causing these other disorders are found in high frequencies in people 00:15:29.825 --> 00:15:35.210 with ancestors from parts of the world that have historically had high rates of malaria, 00:15:35.210 --> 00:15:41.075 but are extremely rare among people without ancestry from those areas. 00:15:41.075 --> 00:15:43.190 NARRATOR: In evolutionary terms, 00:15:43.190 --> 00:15:46.370 these differences in allele frequencies reflect that 00:15:46.370 --> 00:15:50.750 specific mutations in these genes confer a net advantage 00:15:50.750 --> 00:15:54.500 in areas with high incidence of malaria and are 00:15:54.500 --> 00:15:58.955 favored by natural selection over generations in a population, 00:15:58.955 --> 00:16:02.360 whereas they confer a disadvantage and are disfavored 00:16:02.360 --> 00:16:06.320 by natural selection in environments without malaria. 00:16:06.320 --> 00:16:12.150 DR. ARCHER: It's clear that malaria has had a profound effect on human biology. 00:16:17.710 --> 00:16:20.870 MATHEW GLARUM: Right now, I'm in nursing school, 00:16:20.870 --> 00:16:24.740 so I'll be graduating as a nurse at the end of this year. 00:16:24.740 --> 00:16:28.280 I think it will be beneficial for me, 00:16:28.280 --> 00:16:29.510 especially as a nurse, 00:16:29.510 --> 00:16:33.060 knowing what it's like to be in that hospital bed. 00:16:39.370 --> 00:16:43.440 DR. ARCHER: Hey, Morgan, I'm ready for you. 00:16:46.450 --> 00:16:51.215 MORGAN GRACE: I don't let having sickle cell stop me at all. 00:16:51.215 --> 00:16:53.555 I'm still going to do the things that I want to do. 00:16:53.555 --> 00:16:55.895 I might just do it with extra precaution. 00:16:55.895 --> 00:16:59.795 I think it's made me a really more determined person. 00:16:59.795 --> 00:17:04.175 It doesn't matter if I have a week-long hospital stay, 00:17:04.175 --> 00:17:09.210 I just need to get it done and do the best that I can. 00:17:09.670 --> 00:17:12.770 DR. ARCHER: So tell me how you're feeling? 00:17:12.770 --> 00:17:15.050 MORGAN GRACE: I'm feeling pretty good. 00:17:15.050 --> 00:17:17.315 DR. ARCHER: When I talk to my patients, 00:17:17.315 --> 00:17:19.475 I start by discussing the biology. 00:17:19.475 --> 00:17:23.345 They inherited these genes and that 00:17:23.345 --> 00:17:28.580 they are part of fighting this global threat, which was malaria. 00:17:28.580 --> 00:17:32.210 Science has helped us understand sickle cell disease, 00:17:32.210 --> 00:17:35.130 and it's the only thing that's going to help us cure it. 00:17:35.800 --> 00:17:40.790 I am very confident that we will eventually tackle this problem. 00:17:40.790 --> 00:17:42.590 I'll see you in a couple of months. 00:17:42.590 --> 00:17:47.210 Don't forget to schedule your visit and call me if you need me, okay? 00:17:47.210 --> 00:18:27.242 Alright, bye!