1 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. 2 00:00:30,660 --> 00:00:33,840 I have danced since I can remember. 3 00:00:33,840 --> 00:00:36,525 Whenever I hear any kind of music, 4 00:00:36,525 --> 00:00:38,920 I can't just sit still. 5 00:00:40,850 --> 00:00:44,470 I loved being on stage. 6 00:00:46,750 --> 00:00:51,990 It started to like get worse as I was going through puberty. 7 00:00:52,470 --> 00:00:58,970 But I just remember a wave of pain washed over my body. 8 00:00:58,970 --> 00:01:02,490 When I go through a bad pain crisis, 9 00:01:02,490 --> 00:01:05,110 they come out of nowhere. 10 00:01:06,070 --> 00:01:13,470 I had to quit dancing because of being in the hospital. 11 00:01:13,620 --> 00:01:19,350 It just made a lot of things in my life have to stop. 12 00:01:19,730 --> 00:01:22,210 MORGAN'S MOM: Morgan! 13 00:01:24,980 --> 00:01:28,700 Narrator: Morgan has sickle cell disease, 14 00:01:28,700 --> 00:01:33,260 an inherited condition that affects her red blood cells. 15 00:01:34,020 --> 00:01:40,740 Before modern medicine, many people with this disease didn't survive into adulthood. 16 00:01:41,180 --> 00:01:48,000 The theory of evolution by natural selection predicts that harmful traits should be rare. 17 00:01:48,000 --> 00:01:53,340 But what's so puzzling about sickle cell is that it's relatively common, 18 00:01:53,340 --> 00:01:57,740 especially in people with ancestry from certain parts of the world. 19 00:01:57,740 --> 00:02:03,800 Figuring out why this harmful trait is so common will take us on a remarkable journey 20 00:02:03,800 --> 00:02:26,050 of scientific discovery. 21 00:02:26,050 --> 00:02:27,850 NURSE: Dr. Acher will see you. 22 00:02:31,760 --> 00:02:36,760 DR. NATASHA ARCHER: Hematology is the study of blood disorders. 23 00:02:37,640 --> 00:02:45,480 A pediatric hematologist takes care of children with those blood disorders. 24 00:02:45,480 --> 00:02:48,080 Hi. How are you? 25 00:02:48,080 --> 00:02:48,590 MORGAN GRACE: I'm good. 26 00:02:48,590 --> 00:02:49,700 DR. ARCHER: You started school already? 27 00:02:49,700 --> 00:02:51,340 MORGAN GRACE: Yes, I started last week. 28 00:02:51,340 --> 00:02:53,620 DR. ARCHER: I really got interested in hematology when 29 00:02:53,620 --> 00:02:57,510 I started to meet patients who had sickle cell disease. 30 00:02:58,240 --> 00:03:04,280 NARRATOR: Sickle cell disease is caused by a change or mutation in a single gene. 31 00:03:04,280 --> 00:03:08,640 The gene codes for a subunit of the protein hemoglobin, 32 00:03:08,640 --> 00:03:12,420 the protein in red blood cells that binds oxygen. 33 00:03:12,420 --> 00:03:16,060 A mutation in a single nucleotide in the gene 34 00:03:16,060 --> 00:03:19,960 causes a single amino acid change in each subunit, 35 00:03:19,960 --> 00:03:23,140 which in turn causes the hemoglobin molecules to 36 00:03:23,140 --> 00:03:26,745 stick together and change the shape of the red blood cells. 37 00:03:26,745 --> 00:03:28,780 DR. ARCHER: Typically, red blood cells have 38 00:03:28,780 --> 00:03:33,615 this disc shape to them that enable them to move throughout the body with ease. 39 00:03:33,615 --> 00:03:38,465 Sickle cell disease makes the red blood cells a little bit more rigid, 40 00:03:38,465 --> 00:03:43,550 so changes the shape and makes it like a crescent moon or sickle shape. 41 00:03:43,550 --> 00:03:48,570 That rigidity of the red blood cell causes them to block blood vessels, 42 00:03:48,570 --> 00:03:51,550 not allowing blood to get to different parts of the body, 43 00:03:51,550 --> 00:03:54,290 causing severe and debilitating pain. 44 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. 45 00:04:00,920 --> 00:04:06,265 Thinking of your worst pain and not being able to do anything about it, really. 46 00:04:06,265 --> 00:04:09,310 You're doing great. Keep up the good work. 47 00:04:09,310 --> 00:04:11,090 You've taken your medicine, 48 00:04:11,090 --> 00:04:13,830 and I'll see you in 3 months. 49 00:04:15,740 --> 00:04:20,160 MORGAN GRACE: In kindergarten, we had this book. 50 00:04:20,160 --> 00:04:23,170 It's about this young girl with sickle cell, 51 00:04:23,170 --> 00:04:24,830 but she didn't really know what it was. 52 00:04:24,830 --> 00:04:28,410 She just ended up in the hospital quite often. 53 00:04:28,730 --> 00:04:34,010 I could remember having that feeling like I'm in the hospital, 54 00:04:34,010 --> 00:04:36,330 but I don't really know why. 55 00:04:40,100 --> 00:04:43,600 It was really just a lot. 56 00:04:48,980 --> 00:04:52,160 NARRATOR: American researchers first began to study 57 00:04:52,160 --> 00:04:55,365 sickle cell diseases in the early 20th century. 58 00:04:55,365 --> 00:05:00,580 DR. ARCHER: In the US, it was most common among individuals of African ancestry. 59 00:05:00,580 --> 00:05:05,370 They assumed that it was a condition from Africa. 60 00:05:05,370 --> 00:05:10,060 NARRATOR: But no one could explain why sickle cell would be more common in Africa. 61 00:05:10,060 --> 00:05:12,760 Then in the early 1950s, 62 00:05:12,760 --> 00:05:16,340 a Kenyan medical student named Tony Allison made 63 00:05:16,340 --> 00:05:18,260 a surprising discovery while conducting 64 00:05:18,260 --> 00:05:21,510 research on different blood type groups in East Africa. 65 00:05:21,510 --> 00:05:26,570 TONY ALLISON: I actually learned just before going out about the sickle cell condition. 66 00:05:26,570 --> 00:05:31,075 Nobody really knew the frequencies of sickle cells in East Africa. 67 00:05:31,075 --> 00:05:35,410 NARRATOR: Allison wanted to measure the frequencies of the sickle cell allele. 68 00:05:35,410 --> 00:05:39,070 He knew that we inherit 2 copies of most of our genes, 69 00:05:39,070 --> 00:05:42,310 1 from each of our biological parents. 70 00:05:42,310 --> 00:05:46,950 These copies called alleles can be the same or different. 71 00:05:46,950 --> 00:05:52,410 People with 2 copies of the allele without the sickle cell mutation are homozygous, 72 00:05:52,410 --> 00:05:55,410 which means their alleles are the same. 73 00:05:55,410 --> 00:05:59,590 They have round red blood cells and they don't have sickle cell disease. 74 00:05:59,590 --> 00:06:04,670 People with 2 copies of the allele with the mutation are also homozygous, 75 00:06:04,670 --> 00:06:07,005 but for the sickle cell allele. 76 00:06:07,005 --> 00:06:11,920 Many of their red blood cells are sickled and they have sickle cell disease. 77 00:06:11,920 --> 00:06:16,100 People with 1 allele with the sickle cell mutation and 1 allele 78 00:06:16,100 --> 00:06:22,160 without are heterozygous and have what scientists call sickle cell trait. 79 00:06:22,160 --> 00:06:25,940 Under most circumstances, their red blood cells 80 00:06:25,940 --> 00:06:29,920 are round and they don't have any symptoms of the disease. 81 00:06:29,920 --> 00:06:33,280 At the time Tony Allison did his research, 82 00:06:33,280 --> 00:06:36,600 there was no genetic test for sickle cell mutation. 83 00:06:36,600 --> 00:06:40,940 All he could do was look at the blood cells of individuals. 84 00:06:42,020 --> 00:06:45,470 DR. ARCHER: Tony Allison's major challenge 85 00:06:45,470 --> 00:06:48,770 was really trying to identify who were the heterozygous. 86 00:06:48,770 --> 00:06:52,930 It's only in prolonged low oxygen environments 87 00:06:52,930 --> 00:06:56,140 that their blood cells actually become sickled. 88 00:06:57,080 --> 00:07:01,530 Here's the blood of a patient with a sickle cell trait. 89 00:07:01,530 --> 00:07:05,290 They have only 1 sickle cell allele copy. 90 00:07:05,290 --> 00:07:08,170 If you look at this patient's blood under the microscope, 91 00:07:08,170 --> 00:07:11,590 it looks completely normal under normal conditions. 92 00:07:11,590 --> 00:07:14,750 NARRATOR: Researchers can mix a chemical agent to that drop 93 00:07:14,750 --> 00:07:18,630 of blood which creates a low oxygen environment. 94 00:07:19,000 --> 00:07:21,280 After a few hours, 95 00:07:21,280 --> 00:07:24,000 the red blood cells start to sickle. 96 00:07:24,000 --> 00:07:27,900 This allows researchers to distinguish between someone with 97 00:07:27,900 --> 00:07:32,720 no sickle cell alleles and someone with sickle cell trait. 98 00:07:32,720 --> 00:07:35,760 Allison used this simple test to measure 99 00:07:35,760 --> 00:07:39,785 the frequency of sickle cell traits in some parts of Kenya. 100 00:07:39,785 --> 00:07:43,515 TONY ALLISON: You could do it in the field, and I did. 101 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. 102 00:07:51,020 --> 00:07:54,040 NARRATOR: After analyzing hundreds of samples, 103 00:07:54,040 --> 00:07:57,200 an interesting geographic pattern started to emerge. 104 00:07:57,200 --> 00:08:03,140 TONY ALLISON: But what was striking was that you had high frequencies of people carrying 105 00:08:03,140 --> 00:08:06,440 the sickle cell character in the coast and near 106 00:08:06,440 --> 00:08:11,560 Lake Victoria and very low frequencies in the high country in between, in Nairobi. 107 00:08:11,560 --> 00:08:14,730 NARRATOR: In the lowlands, 108 00:08:14,730 --> 00:08:18,230 the sickle cell trait frequencies were over 20 percent. 109 00:08:18,230 --> 00:08:19,590 Whereas in the highlands, 110 00:08:19,590 --> 00:08:22,930 the frequencies were less than 1 percent. 111 00:08:22,930 --> 00:08:27,770 What could explain such dramatic differences between these regions? 112 00:08:27,770 --> 00:08:31,610 A childhood memory helped Tony make the connection. 113 00:08:31,610 --> 00:08:34,130 Allison had caught malaria, 114 00:08:34,130 --> 00:08:38,930 a deadly infectious disease on a family vacation to the Kenyan coast. 115 00:08:38,930 --> 00:08:42,430 He knew very well that the humid lowlands around 116 00:08:42,430 --> 00:08:46,150 Lake Victoria are breeding grounds for the Anopheles mosquito, 117 00:08:46,150 --> 00:08:49,370 which spread the malaria parasite. 118 00:08:50,210 --> 00:08:54,050 Allison also knew that these mosquitoes, and 119 00:08:54,050 --> 00:08:58,010 the malaria they spread, are not common in the drier highlands. 120 00:08:58,010 --> 00:09:01,960 Could sickle cell and malaria somehow be connected? 121 00:09:01,960 --> 00:09:05,450 TONY ALLISON: If that's the case, you predict that you have 122 00:09:05,450 --> 00:09:10,125 high frequencies of sickle cells only in areas where malaria is endemic. 123 00:09:10,125 --> 00:09:12,190 NARRATOR: To test this hypothesis, 124 00:09:12,190 --> 00:09:16,190 Allison needed data from more people and a larger area. 125 00:09:16,190 --> 00:09:19,970 He visited markets and villages throughout Uganda, Kenya, 126 00:09:19,970 --> 00:09:24,730 and Tanzania, offering checkups and medicine to the people in those markets. 127 00:09:24,730 --> 00:09:30,130 During these checkups, he collected about 5,000 blood samples. 128 00:09:30,130 --> 00:09:34,110 The research of Allison and others confirmed that there is 129 00:09:34,110 --> 00:09:39,485 a strong correlation between the frequency of sickle cell trait and malaria. 130 00:09:39,485 --> 00:09:43,040 Tony wondered if having a sickle cell allele 131 00:09:43,040 --> 00:09:47,320 offered an advantage to people living in areas with malaria. 132 00:09:47,320 --> 00:09:50,395 How could he test this hypothesis? 133 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, 134 00:09:56,160 --> 00:09:58,460 in fact, protected against malaria. 135 00:09:58,460 --> 00:10:01,700 NARRATOR: He collected blood samples from children aged 136 00:10:01,700 --> 00:10:06,560 5 months to 5 years and analyzed them under a microscope. 137 00:10:06,560 --> 00:10:12,115 In each sample, he counted the number of parasites that caused malaria. 138 00:10:12,115 --> 00:10:15,160 He then compared the parasite counts in 139 00:10:15,160 --> 00:10:19,290 children with sickle cell trait to those without. 140 00:10:21,250 --> 00:10:25,950 TONY ALLISON: The sickle cell trait would have lower parasite counts. 141 00:10:27,070 --> 00:10:31,565 NARRATOR: This was the strongest evidence yet that the sickle cell trait 142 00:10:31,565 --> 00:10:36,270 gave heterozygotes an advantage where malaria was present. 143 00:10:38,230 --> 00:10:41,750 People with no sickle cell allele were less 144 00:10:41,750 --> 00:10:45,660 likely to survive and reproduce due to malaria. 145 00:10:45,970 --> 00:10:50,090 People with 2 sickle cell alleles were less likely to 146 00:10:50,090 --> 00:10:54,185 survive and reproduce due to sickle cell disease. 147 00:10:54,185 --> 00:11:00,185 But people with one sickle cell allele were more likely to survive and reproduce. 148 00:11:00,185 --> 00:11:06,620 Tony Allison had discovered the first clear example of natural selection in humans, 149 00:11:06,620 --> 00:11:11,555 but how did the sickle cell allele protect people from malaria? 150 00:11:11,555 --> 00:11:16,010 TONY ALLISON: I have to say, I left that part of this story to 151 00:11:16,010 --> 00:11:20,970 others because it's quite a complex story. 152 00:11:21,700 --> 00:11:28,295 NARRATOR: The parasite that causes malaria feeds on hemoglobin inside red blood cells. 153 00:11:28,295 --> 00:11:33,230 Natasha Archer studies how the sickle cell trait affects this process. 154 00:11:33,230 --> 00:11:35,105 DR. ARCHER: When a mosquito bites you, 155 00:11:35,105 --> 00:11:38,750 the parasite makes its way into the red blood cells. 156 00:11:38,750 --> 00:11:43,955 Eventually, it releases these proteins that attach to 157 00:11:43,955 --> 00:11:49,250 blood vessels and force the red blood cell to stay in one location. 158 00:11:49,250 --> 00:11:53,045 What's unique about the blood vessels that it sticks 159 00:11:53,045 --> 00:11:57,830 to is that those environments typically have low oxygen. 160 00:11:57,830 --> 00:12:01,310 If you remember, individuals with sickle cell trait, 161 00:12:01,310 --> 00:12:06,740 their red blood cells sickle if they are in prolonged low oxygen environments. 162 00:12:06,740 --> 00:12:13,670 The malaria parasite now will not have hemoglobin that's as easily digestible. 163 00:12:13,670 --> 00:12:16,400 NARRATOR: Without hemoglobin to feed on, 164 00:12:16,400 --> 00:12:20,735 malaria parasites can't grow or reproduce as quickly. 165 00:12:20,735 --> 00:12:25,070 DR. ARCHER: Our research takes us one step further in understanding 166 00:12:25,070 --> 00:12:30,305 how sickle cell trait is protective against malaria. 167 00:12:30,305 --> 00:12:35,030 NARRATOR: Malaria occurred in many regions around the world. 168 00:12:35,030 --> 00:12:43,050 Does the pattern Tony Allison observed in East Africa also occur in these other regions? 169 00:12:48,970 --> 00:12:54,320 MATHEW GLARUM: What I love about playing music is that when I am up there playing, 170 00:12:54,320 --> 00:12:56,990 there's nothing but that. That's my therapy. 171 00:12:56,990 --> 00:13:05,690 'Cause I can’t hold her anymore. Can’t pass the time. 172 00:13:05,690 --> 00:13:10,670 According to my grandma, I was begging her for guitar lessons at 5-years-old. 173 00:13:10,670 --> 00:13:14,340 It's always been around in my life, instruments and stuff. 174 00:13:26,230 --> 00:13:28,565 When I was born, 175 00:13:28,565 --> 00:13:31,640 my mom knew to look out for us 176 00:13:31,640 --> 00:13:36,785 potentially having sickle cell because my brother, 177 00:13:36,785 --> 00:13:39,060 he was born with it. 178 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, 179 00:13:47,000 --> 00:13:50,790 we could get pain, get taken to the hospital. 180 00:13:54,610 --> 00:13:58,220 We couldn't participate in holidays, 181 00:13:58,220 --> 00:14:01,985 family vacations, and we couldn't go to school. 182 00:14:01,985 --> 00:14:04,310 That gets in the way a little bit. 183 00:14:04,310 --> 00:14:08,225 Now, as an adult, I've had experiences where my sickle cell 184 00:14:08,225 --> 00:14:12,870 and getting into a crisis has messed up important stuff. 185 00:14:13,540 --> 00:14:19,655 My mom's part of the family comes from the Mediterranean area in Sicily. 186 00:14:19,655 --> 00:14:23,970 Then my dad is from Norway and then Belize. 187 00:14:24,160 --> 00:14:27,830 DR. ARCHER: When we look at the people who carry the sickle cell allele, 188 00:14:27,830 --> 00:14:31,820 they share recent ancestry with regions that have historically experienced 189 00:14:31,820 --> 00:14:36,935 high rates of malaria like sub Saharan Africa, Greece, Italy. 190 00:14:36,935 --> 00:14:40,265 NARRATOR: Several studies have shown that throughout the world, 191 00:14:40,265 --> 00:14:44,360 the frequency of the sickle cell allele tends to be lower in areas with 192 00:14:44,360 --> 00:14:49,055 little to no malaria and higher in areas with a lot of malaria, 193 00:14:49,055 --> 00:14:53,630 similar to what Tony Allison and other researchers observed in Africa. 194 00:14:53,630 --> 00:14:57,050 Scientists have observed similar patterns with 195 00:14:57,050 --> 00:15:01,500 other inherited conditions that affect red blood cells. 196 00:15:01,630 --> 00:15:05,345 DR. ARCHER: I also treat patients who have mutations in other genes, 197 00:15:05,345 --> 00:15:07,805 which cause diseases like ovalcytosis, 198 00:15:07,805 --> 00:15:12,185 Thalassemia, G6PD enzyme deficiency and others. 199 00:15:12,185 --> 00:15:18,035 NARRATOR: Mutations in these genes also make it harder for the malaria parasite to infect, 200 00:15:18,035 --> 00:15:22,130 survive, or reproduce in red blood cells. 201 00:15:22,130 --> 00:15:24,470 DR. ARCHER: Just like the sickle cell allele, 202 00:15:24,470 --> 00:15:29,825 all of the alleles causing these other disorders are found in high frequencies in people 203 00:15:29,825 --> 00:15:35,210 with ancestors from parts of the world that have historically had high rates of malaria, 204 00:15:35,210 --> 00:15:41,075 but are extremely rare among people without ancestry from those areas. 205 00:15:41,075 --> 00:15:43,190 NARRATOR: In evolutionary terms, 206 00:15:43,190 --> 00:15:46,370 these differences in allele frequencies reflect that 207 00:15:46,370 --> 00:15:50,750 specific mutations in these genes confer a net advantage 208 00:15:50,750 --> 00:15:54,500 in areas with high incidence of malaria and are 209 00:15:54,500 --> 00:15:58,955 favored by natural selection over generations in a population, 210 00:15:58,955 --> 00:16:02,360 whereas they confer a disadvantage and are disfavored 211 00:16:02,360 --> 00:16:06,320 by natural selection in environments without malaria. 212 00:16:06,320 --> 00:16:12,150 DR. ARCHER: It's clear that malaria has had a profound effect on human biology. 213 00:16:17,710 --> 00:16:20,870 MATHEW GLARUM: Right now, I'm in nursing school, 214 00:16:20,870 --> 00:16:24,740 so I'll be graduating as a nurse at the end of this year. 215 00:16:24,740 --> 00:16:28,280 I think it will be beneficial for me, 216 00:16:28,280 --> 00:16:29,510 especially as a nurse, 217 00:16:29,510 --> 00:16:33,060 knowing what it's like to be in that hospital bed. 218 00:16:39,370 --> 00:16:43,440 DR. ARCHER: Hey, Morgan, I'm ready for you. 219 00:16:46,450 --> 00:16:51,215 MORGAN GRACE: I don't let having sickle cell stop me at all. 220 00:16:51,215 --> 00:16:53,555 I'm still going to do the things that I want to do. 221 00:16:53,555 --> 00:16:55,895 I might just do it with extra precaution. 222 00:16:55,895 --> 00:16:59,795 I think it's made me a really more determined person. 223 00:16:59,795 --> 00:17:04,175 It doesn't matter if I have a week-long hospital stay, 224 00:17:04,175 --> 00:17:09,210 I just need to get it done and do the best that I can. 225 00:17:09,670 --> 00:17:12,770 DR. ARCHER: So tell me how you're feeling? 226 00:17:12,770 --> 00:17:15,050 MORGAN GRACE: I'm feeling pretty good. 227 00:17:15,050 --> 00:17:17,315 DR. ARCHER: When I talk to my patients, 228 00:17:17,315 --> 00:17:19,475 I start by discussing the biology. 229 00:17:19,475 --> 00:17:23,345 They inherited these genes and that 230 00:17:23,345 --> 00:17:28,580 they are part of fighting this global threat, which was malaria. 231 00:17:28,580 --> 00:17:32,210 Science has helped us understand sickle cell disease, 232 00:17:32,210 --> 00:17:35,130 and it's the only thing that's going to help us cure it. 233 00:17:35,800 --> 00:17:40,790 I am very confident that we will eventually tackle this problem. 234 00:17:40,790 --> 00:17:42,590 I'll see you in a couple of months. 235 00:17:42,590 --> 00:17:47,210 Don't forget to schedule your visit and call me if you need me, okay? 236 00:17:47,210 --> 00:18:27,242 Alright, bye!