0:00:21.380,0:00:30.660 MORGAN GRACE: I think I kind of always knew that I had something different than other kids. 0:00:30.660,0:00:33.840 I have danced since I can remember. 0:00:33.840,0:00:36.525 Whenever I hear any kind of music, 0:00:36.525,0:00:38.920 I can't just sit still. 0:00:40.850,0:00:44.470 I loved being on stage. 0:00:46.750,0:00:51.990 It started to like get worse as I was going through puberty. 0:00:52.470,0:00:58.970 But I just remember a wave of pain washed over my body. 0:00:58.970,0:01:02.490 When I go through a bad pain crisis, 0:01:02.490,0:01:05.110 they come out of nowhere. 0:01:06.070,0:01:13.470 I had to quit dancing because of being in the hospital. 0:01:13.620,0:01:19.350 It just made a lot of things in my life have to stop. 0:01:19.730,0:01:22.210 MORGAN'S MOM: Morgan! 0:01:24.980,0:01:28.700 Narrator: Morgan has sickle cell disease, 0:01:28.700,0:01:33.260 an inherited condition that affects her red blood cells. 0:01:34.020,0:01:40.740 Before modern medicine, many people with this disease didn't survive into adulthood. 0:01:41.180,0:01:48.000 The theory of evolution by natural selection predicts that harmful traits should be rare. 0:01:48.000,0:01:53.340 But what's so puzzling about sickle cell is that it's relatively common, 0:01:53.340,0:01:57.740 especially in people with ancestry from certain parts of the world. 0:01:57.740,0:02:03.800 Figuring out why this harmful trait is so common will take us on a remarkable journey 0:02:03.800,0:02:26.050 of scientific discovery. 0:02:26.050,0:02:27.850 NURSE: Dr. Acher will see you. 0:02:31.760,0:02:36.760 DR. NATASHA ARCHER: Hematology is the study of blood disorders. 0:02:37.640,0:02:45.480 A pediatric hematologist takes care of children with those blood disorders. 0:02:45.480,0:02:48.080 Hi. How are you? 0:02:48.080,0:02:48.590 MORGAN GRACE: I'm good. 0:02:48.590,0:02:49.700 DR. ARCHER: You started school already? 0:02:49.700,0:02:51.340 MORGAN GRACE: Yes, I started last week. 0:02:51.340,0:02:53.620 DR. ARCHER: I really got interested in hematology when 0:02:53.620,0:02:57.510 I started to meet patients who had sickle cell disease. 0:02:58.240,0:03:04.280 NARRATOR: Sickle cell disease is caused by a change or mutation in a single gene. 0:03:04.280,0:03:08.640 The gene codes for a subunit of the protein hemoglobin, 0:03:08.640,0:03:12.420 the protein in red blood cells that binds oxygen. 0:03:12.420,0:03:16.060 A mutation in a single nucleotide in the gene 0:03:16.060,0:03:19.960 causes a single amino acid change in each subunit, 0:03:19.960,0:03:23.140 which in turn causes the hemoglobin molecules to 0:03:23.140,0:03:26.745 stick together and change the shape of the red blood cells. 0:03:26.745,0:03:28.780 DR. ARCHER: Typically, red blood cells have 0:03:28.780,0:03:33.615 this disc shape to them that enable them to move throughout the body with ease. 0:03:33.615,0:03:38.465 Sickle cell disease makes the red blood cells a little bit more rigid, 0:03:38.465,0:03:43.550 so changes the shape and makes it like a crescent moon or sickle shape. 0:03:43.550,0:03:48.570 That rigidity of the red blood cell causes them to block blood vessels, 0:03:48.570,0:03:51.550 not allowing blood to get to different parts of the body, 0:03:51.550,0:03:54.290 causing severe and debilitating pain. 0:03:54.290,0:04:00.920 For a pain crisis, my patients typically describe it as a pain that won't go away. 0:04:00.920,0:04:06.265 Thinking of your worst pain and not being able to do anything about it, really. 0:04:06.265,0:04:09.310 You're doing great. Keep up the good work. 0:04:09.310,0:04:11.090 You've taken your medicine, 0:04:11.090,0:04:13.830 and I'll see you in 3 months. 0:04:15.740,0:04:20.160 MORGAN GRACE: In kindergarten, we had this book. 0:04:20.160,0:04:23.170 It's about this young girl with sickle cell, 0:04:23.170,0:04:24.830 but she didn't really know what it was. 0:04:24.830,0:04:28.410 She just ended up in the hospital quite often. 0:04:28.730,0:04:34.010 I could remember having that feeling like I'm in the hospital, 0:04:34.010,0:04:36.330 but I don't really know why. 0:04:40.100,0:04:43.600 It was really just a lot. 0:04:48.980,0:04:52.160 NARRATOR: American researchers first began to study 0:04:52.160,0:04:55.365 sickle cell diseases in the early 20th century. 0:04:55.365,0:05:00.580 DR. ARCHER: In the US, it was most common among individuals of African ancestry. 0:05:00.580,0:05:05.370 They assumed that it was a condition from Africa. 0:05:05.370,0:05:10.060 NARRATOR: But no one could explain why sickle cell would be more common in Africa. 0:05:10.060,0:05:12.760 Then in the early 1950s, 0:05:12.760,0:05:16.340 a Kenyan medical student named Tony Allison made 0:05:16.340,0:05:18.260 a surprising discovery while conducting 0:05:18.260,0:05:21.510 research on different blood type groups in East Africa. 0:05:21.510,0:05:26.570 TONY ALLISON: I actually learned just before going out about the sickle cell condition. 0:05:26.570,0:05:31.075 Nobody really knew the frequencies of sickle cells in East Africa. 0:05:31.075,0:05:35.410 NARRATOR: Allison wanted to measure the frequencies of the sickle cell allele. 0:05:35.410,0:05:39.070 He knew that we inherit 2 copies of most of our genes, 0:05:39.070,0:05:42.310 1 from each of our biological parents. 0:05:42.310,0:05:46.950 These copies called alleles can be the same or different. 0:05:46.950,0:05:52.410 People with 2 copies of the allele without the sickle cell mutation are homozygous, 0:05:52.410,0:05:55.410 which means their alleles are the same. 0:05:55.410,0:05:59.590 They have round red blood cells and they don't have sickle cell disease. 0:05:59.590,0:06:04.670 People with 2 copies of the allele with the mutation are also homozygous, 0:06:04.670,0:06:07.005 but for the sickle cell allele. 0:06:07.005,0:06:11.920 Many of their red blood cells are sickled and they have sickle cell disease. 0:06:11.920,0:06:16.100 People with 1 allele with the sickle cell mutation and 1 allele 0:06:16.100,0:06:22.160 without are heterozygous and have what scientists call sickle cell trait. 0:06:22.160,0:06:25.940 Under most circumstances, their red blood cells 0:06:25.940,0:06:29.920 are round and they don't have any symptoms of the disease. 0:06:29.920,0:06:33.280 At the time Tony Allison did his research, 0:06:33.280,0:06:36.600 there was no genetic test for sickle cell mutation. 0:06:36.600,0:06:40.940 All he could do was look at the blood cells of individuals. 0:06:42.020,0:06:45.470 DR. ARCHER: Tony Allison's major challenge 0:06:45.470,0:06:48.770 was really trying to identify who were the heterozygous. 0:06:48.770,0:06:52.930 It's only in prolonged low oxygen environments 0:06:52.930,0:06:56.140 that their blood cells actually become sickled. 0:06:57.080,0:07:01.530 Here's the blood of a patient with a sickle cell trait. 0:07:01.530,0:07:05.290 They have only 1 sickle cell allele copy. 0:07:05.290,0:07:08.170 If you look at this patient's blood under the microscope, 0:07:08.170,0:07:11.590 it looks completely normal under normal conditions. 0:07:11.590,0:07:14.750 NARRATOR: Researchers can mix a chemical agent to that drop 0:07:14.750,0:07:18.630 of blood which creates a low oxygen environment. 0:07:19.000,0:07:21.280 After a few hours, 0:07:21.280,0:07:24.000 the red blood cells start to sickle. 0:07:24.000,0:07:27.900 This allows researchers to distinguish between someone with 0:07:27.900,0:07:32.720 no sickle cell alleles and someone with sickle cell trait. 0:07:32.720,0:07:35.760 Allison used this simple test to measure 0:07:35.760,0:07:39.785 the frequency of sickle cell traits in some parts of Kenya. 0:07:39.785,0:07:43.515 TONY ALLISON: You could do it in the field, and I did. 0:07:43.515,0:07:51.020 I had a little traveling microscope run off a small bulb that came from a car battery. 0:07:51.020,0:07:54.040 NARRATOR: After analyzing hundreds of samples, 0:07:54.040,0:07:57.200 an interesting geographic pattern started to emerge. 0:07:57.200,0:08:03.140 TONY ALLISON: But what was striking was that you had high frequencies of people carrying 0:08:03.140,0:08:06.440 the sickle cell character in the coast and near 0:08:06.440,0:08:11.560 Lake Victoria and very low frequencies in the high country in between, in Nairobi. 0:08:11.560,0:08:14.730 NARRATOR: In the lowlands, 0:08:14.730,0:08:18.230 the sickle cell trait frequencies were over 20 percent. 0:08:18.230,0:08:19.590 Whereas in the highlands, 0:08:19.590,0:08:22.930 the frequencies were less than 1 percent. 0:08:22.930,0:08:27.770 What could explain such dramatic differences between these regions? 0:08:27.770,0:08:31.610 A childhood memory helped Tony make the connection. 0:08:31.610,0:08:34.130 Allison had caught malaria, 0:08:34.130,0:08:38.930 a deadly infectious disease on a family vacation to the Kenyan coast. 0:08:38.930,0:08:42.430 He knew very well that the humid lowlands around 0:08:42.430,0:08:46.150 Lake Victoria are breeding grounds for the Anopheles mosquito, 0:08:46.150,0:08:49.370 which spread the malaria parasite. 0:08:50.210,0:08:54.050 Allison also knew that these mosquitoes, and 0:08:54.050,0:08:58.010 the malaria they spread, are not common in the drier highlands. 0:08:58.010,0:09:01.960 Could sickle cell and malaria somehow be connected? 0:09:01.960,0:09:05.450 TONY ALLISON: If that's the case, you predict that you have 0:09:05.450,0:09:10.125 high frequencies of sickle cells only in areas where malaria is endemic. 0:09:10.125,0:09:12.190 NARRATOR: To test this hypothesis, 0:09:12.190,0:09:16.190 Allison needed data from more people and a larger area. 0:09:16.190,0:09:19.970 He visited markets and villages throughout Uganda, Kenya, 0:09:19.970,0:09:24.730 and Tanzania, offering checkups and medicine to the people in those markets. 0:09:24.730,0:09:30.130 During these checkups, he collected about 5,000 blood samples. 0:09:30.130,0:09:34.110 The research of Allison and others confirmed that there is 0:09:34.110,0:09:39.485 a strong correlation between the frequency of sickle cell trait and malaria. 0:09:39.485,0:09:43.040 Tony wondered if having a sickle cell allele 0:09:43.040,0:09:47.320 offered an advantage to people living in areas with malaria. 0:09:47.320,0:09:50.395 How could he test this hypothesis? 0:09:50.395,0:09:56.160 TONY ALLISON: You look at malaria in children of the appropriate age and find out whether they are, 0:09:56.160,0:09:58.460 in fact, protected against malaria. 0:09:58.460,0:10:01.700 NARRATOR: He collected blood samples from children aged 0:10:01.700,0:10:06.560 5 months to 5 years and analyzed them under a microscope. 0:10:06.560,0:10:12.115 In each sample, he counted the number of parasites that caused malaria. 0:10:12.115,0:10:15.160 He then compared the parasite counts in 0:10:15.160,0:10:19.290 children with sickle cell trait to those without. 0:10:21.250,0:10:25.950 TONY ALLISON: The sickle cell trait would have lower parasite counts. 0:10:27.070,0:10:31.565 NARRATOR: This was the strongest evidence yet that the sickle cell trait 0:10:31.565,0:10:36.270 gave heterozygotes an advantage where malaria was present. 0:10:38.230,0:10:41.750 People with no sickle cell allele were less 0:10:41.750,0:10:45.660 likely to survive and reproduce due to malaria. 0:10:45.970,0:10:50.090 People with 2 sickle cell alleles were less likely to 0:10:50.090,0:10:54.185 survive and reproduce due to sickle cell disease. 0:10:54.185,0:11:00.185 But people with one sickle cell allele were more likely to survive and reproduce. 0:11:00.185,0:11:06.620 Tony Allison had discovered the first clear example of natural selection in humans, 0:11:06.620,0:11:11.555 but how did the sickle cell allele protect people from malaria? 0:11:11.555,0:11:16.010 TONY ALLISON: I have to say, I left that part of this story to 0:11:16.010,0:11:20.970 others because it's quite a complex story. 0:11:21.700,0:11:28.295 NARRATOR: The parasite that causes malaria feeds on hemoglobin inside red blood cells. 0:11:28.295,0:11:33.230 Natasha Archer studies how the sickle cell trait affects this process. 0:11:33.230,0:11:35.105 DR. ARCHER: When a mosquito bites you, 0:11:35.105,0:11:38.750 the parasite makes its way into the red blood cells. 0:11:38.750,0:11:43.955 Eventually, it releases these proteins that attach to 0:11:43.955,0:11:49.250 blood vessels and force the red blood cell to stay in one location. 0:11:49.250,0:11:53.045 What's unique about the blood vessels that it sticks 0:11:53.045,0:11:57.830 to is that those environments typically have low oxygen. 0:11:57.830,0:12:01.310 If you remember, individuals with sickle cell trait, 0:12:01.310,0:12:06.740 their red blood cells sickle if they are in prolonged low oxygen environments. 0:12:06.740,0:12:13.670 The malaria parasite now will not have hemoglobin that's as easily digestible. 0:12:13.670,0:12:16.400 NARRATOR: Without hemoglobin to feed on, 0:12:16.400,0:12:20.735 malaria parasites can't grow or reproduce as quickly. 0:12:20.735,0:12:25.070 DR. ARCHER: Our research takes us one step further in understanding 0:12:25.070,0:12:30.305 how sickle cell trait is protective against malaria. 0:12:30.305,0:12:35.030 NARRATOR: Malaria occurred in many regions around the world. 0:12:35.030,0:12:43.050 Does the pattern Tony Allison observed in East Africa also occur in these other regions? 0:12:48.970,0:12:54.320 MATHEW GLARUM: What I love about playing music is that when I am up there playing, 0:12:54.320,0:12:56.990 there's nothing but that. That's my therapy. 0:12:56.990,0:13:05.690 'Cause I can’t hold her anymore. Can’t pass the time. 0:13:05.690,0:13:10.670 According to my grandma, I was begging her for guitar lessons at 5-years-old. 0:13:10.670,0:13:14.340 It's always been around in my life, instruments and stuff. 0:13:26.230,0:13:28.565 When I was born, 0:13:28.565,0:13:31.640 my mom knew to look out for us 0:13:31.640,0:13:36.785 potentially having sickle cell because my brother, 0:13:36.785,0:13:39.060 he was born with it. 0:13:41.980,0:13:47.000 When you're a kid and all you want to do is have fun with your friends, 0:13:47.000,0:13:50.790 we could get pain, get taken to the hospital. 0:13:54.610,0:13:58.220 We couldn't participate in holidays, 0:13:58.220,0:14:01.985 family vacations, and we couldn't go to school. 0:14:01.985,0:14:04.310 That gets in the way a little bit. 0:14:04.310,0:14:08.225 Now, as an adult, I've had experiences where my sickle cell 0:14:08.225,0:14:12.870 and getting into a crisis has messed up important stuff. 0:14:13.540,0:14:19.655 My mom's part of the family comes from the Mediterranean area in Sicily. 0:14:19.655,0:14:23.970 Then my dad is from Norway and then Belize. 0:14:24.160,0:14:27.830 DR. ARCHER: When we look at the people who carry the sickle cell allele, 0:14:27.830,0:14:31.820 they share recent ancestry with regions that have historically experienced 0:14:31.820,0:14:36.935 high rates of malaria like sub Saharan Africa, Greece, Italy. 0:14:36.935,0:14:40.265 NARRATOR: Several studies have shown that throughout the world, 0:14:40.265,0:14:44.360 the frequency of the sickle cell allele tends to be lower in areas with 0:14:44.360,0:14:49.055 little to no malaria and higher in areas with a lot of malaria, 0:14:49.055,0:14:53.630 similar to what Tony Allison and other researchers observed in Africa. 0:14:53.630,0:14:57.050 Scientists have observed similar patterns with 0:14:57.050,0:15:01.500 other inherited conditions that affect red blood cells. 0:15:01.630,0:15:05.345 DR. ARCHER: I also treat patients who have mutations in other genes, 0:15:05.345,0:15:07.805 which cause diseases like ovalcytosis, 0:15:07.805,0:15:12.185 Thalassemia, G6PD enzyme deficiency and others. 0:15:12.185,0:15:18.035 NARRATOR: Mutations in these genes also make it harder for the malaria parasite to infect, 0:15:18.035,0:15:22.130 survive, or reproduce in red blood cells. 0:15:22.130,0:15:24.470 DR. ARCHER: Just like the sickle cell allele, 0:15:24.470,0:15:29.825 all of the alleles causing these other disorders are found in high frequencies in people 0:15:29.825,0:15:35.210 with ancestors from parts of the world that have historically had high rates of malaria, 0:15:35.210,0:15:41.075 but are extremely rare among people without ancestry from those areas. 0:15:41.075,0:15:43.190 NARRATOR: In evolutionary terms, 0:15:43.190,0:15:46.370 these differences in allele frequencies reflect that 0:15:46.370,0:15:50.750 specific mutations in these genes confer a net advantage 0:15:50.750,0:15:54.500 in areas with high incidence of malaria and are 0:15:54.500,0:15:58.955 favored by natural selection over generations in a population, 0:15:58.955,0:16:02.360 whereas they confer a disadvantage and are disfavored 0:16:02.360,0:16:06.320 by natural selection in environments without malaria. 0:16:06.320,0:16:12.150 DR. ARCHER: It's clear that malaria has had a profound effect on human biology. 0:16:17.710,0:16:20.870 MATHEW GLARUM: Right now, I'm in nursing school, 0:16:20.870,0:16:24.740 so I'll be graduating as a nurse at the end of this year. 0:16:24.740,0:16:28.280 I think it will be beneficial for me, 0:16:28.280,0:16:29.510 especially as a nurse, 0:16:29.510,0:16:33.060 knowing what it's like to be in that hospital bed. 0:16:39.370,0:16:43.440 DR. ARCHER: Hey, Morgan, I'm ready for you. 0:16:46.450,0:16:51.215 MORGAN GRACE: I don't let having sickle cell stop me at all. 0:16:51.215,0:16:53.555 I'm still going to do the things that I want to do. 0:16:53.555,0:16:55.895 I might just do it with extra precaution. 0:16:55.895,0:16:59.795 I think it's made me a really more determined person. 0:16:59.795,0:17:04.175 It doesn't matter if I have a week-long hospital stay, 0:17:04.175,0:17:09.210 I just need to get it done and do the best that I can. 0:17:09.670,0:17:12.770 DR. ARCHER: So tell me how you're feeling? 0:17:12.770,0:17:15.050 MORGAN GRACE: I'm feeling pretty good. 0:17:15.050,0:17:17.315 DR. ARCHER: When I talk to my patients, 0:17:17.315,0:17:19.475 I start by discussing the biology. 0:17:19.475,0:17:23.345 They inherited these genes and that 0:17:23.345,0:17:28.580 they are part of fighting this global threat, which was malaria. 0:17:28.580,0:17:32.210 Science has helped us understand sickle cell disease, 0:17:32.210,0:17:35.130 and it's the only thing that's going to help us cure it. 0:17:35.800,0:17:40.790 I am very confident that we will eventually tackle this problem. 0:17:40.790,0:17:42.590 I'll see you in a couple of months. 0:17:42.590,0:17:47.210 Don't forget to schedule your visit and call me if you need me, okay? 0:17:47.210,0:18:27.242 Alright, bye!