Make a Life to Save a Life

1. Make a Life to Save a Life by Peggy Brickman University of Georgia

2. Jack and Lisa Nash’s daughter Molly was born with a rare, incurable genetic condition called Fanconi anemia, which rendered her body unable to produce enough blood cells… The Case

3. Matching Organs:HLA Finding a correct match for tissue transplantation depends on matching a specific group of proteins found on the surface of white blood cells that are used to distinguish one’s own cells from foreign cells, called HLA, for human leukocyte antigen. 3

4. Matches for Organ Donation • HLA proteins encoded by several genes on chromosome 6. • Many variants of gene = mutations that create differences (alleles) 6

5. foreign cell Macrophage Lysosome digests proteins HLA Proteins Present Foreign Antigens Peptides displayed by HLA proteins

6. HLA: Inherited from Parents Mrs. Nash is diploid = two homologues of chromosome 6 HLA-A1 HLA-A2 HLA-B35 HLA-B44

7. Why do diploid organisms need to have specialized sex cells? • Sex cells (gametes) allow traits to be combined from two organisms. • Can’t just fuse any two random cells. 2n (46) 2n (46) + A1 A2 A3 A26 B35 B44 B41 B35 4n = 92 too many

8. A2 Sexual Reproduction • Meiosis = specialized cell division so you have only one of each chromosome, called • Gametes: (n) made only in gonad (testis, ovary) n (23) n (23) + A26 B35 B44 A2 A26 2n = 46 B44 B35

9. A1 A2 B35 B44 Question 1: When Mrs. Nash produces eggs, they would have which combinations of the HLA-A and HLA-B genes and in what proportions? Explain your answer. 100% B35-A1 50% B35-B44 & 50% A1-A2 50% B35-A1 & 50% B44-A2 100% B44-A2 50% B35-A2, & 50% B44-A1 Mrs. Nash’s chromosome 6s

10. Chromosome Pairing: Synapsis • Close proximity favors crossing over • Allows exchange of traits Exchange of parts of non-sister chromatids Duplicated Maternal chromosome Duplicated Paternal chromosome tetrad sister chromatids non-sister chromatids

11. Sister chromatids Sister chromatids A1 A2 B35 B44 meiosis I mitosis A1 A2 A1 A2 B35 B44 B35 B44 Mitosis Meiosis I A1 A1 B35 B35 Homologues Pair A2 A2 B44 B44 A1 A2 A2 A1 A1 A2 A1 A2 B44 B44 B35 B44 B35 B44 B35 B35

12. Update: Meiosis I completed • Homologous chromosomes are separated into two different cells. • Each new cell has only one of each different chromosome (n, haploid). • Still need to separate the sister chromatids so that the total amount of chromosomes and DNA is truly half of a normal cell.

13. meiosis II meiosis II Meiosis II: Sister chromatids separate End result: Four haploid cells total A1 A2 A2 A1 B44 B44 B35 B35 A1 A1 A2 A2 B35 B35 B44 B44

14. Question 2: When Mr. Nash produces sperm, the sperm would have which combinations of the HLA-A and HLA-B genes and in what proportions? Explain your answer. 100% B5-A26 50% B35-A3 & 50% B41-A26 50% B35-B41 & 50% A3-A26 100% B44-A2 B35-A26 50% B35-A26, & 50% B41-A3 A3 A26 B41 B35 Mr. Nash’s chromosome 6s

15. A1 A2 B35 B44 Question 3: Which of the following shows one combination of HLA-A and HLA-B genes expected in an offspring of Lisa and Jack Nash? Explain your answer. B35, B35, A1, A2 B35, B44, A2, A3 B44, B35, A2, A26 B41, B44, A26, A2 A3 A26 B41 B35 Mrs. Nash Mr. Nash

16. A1 A2 B35 B44 Questions 4: Is it possible for any child born to this couple to be identical in both HLA-A and HLA-B with either parent? • Yes • No A3 A26 B41 B35 Mrs. Nash Mr. Nash

17. Question 5: Using the proportion of each type of sperm and egg that you calculated in questions I and II, what is the likelihood that Molly’s sibling would inherit the same combination of HLA genes and thus be a good organ donor for Molly? Explain using a Punnett square. No chance 25% 50% 75% 100% Chromosome 6s for Molly Nash A2 A26 B44 B35

18. Clearly Molly’s best chance of finding a bone marrow match was with a sibling. Unfortunately, Molly was an only child. The Nashes had always wanted to have more children, but because Fanconi anemia is an inherited condition, they knew that if they had another child that child had a chance of getting the disease just as Molly had. But neither Jack nor Lisa had the disease because the mutation is recessive. In order to have Fanconi anemia like Molly, both copies of the FANCC gene would have to have this recessive mutation, and they only had one.

19. Question 6: Using what you know about how meiosis created eggs and sperm, what is the likelihood that Lisa and Jack Nash could conceive a sibling for Molly that would NOT have Fanconi anemia (presence of at least one normal)? Use a Punnett Square to explain your answer. 0% 25% 50% 75% 100%

20. Pre-Implantation Genetic Screening • When they discovered that they could conceive a baby that was free from Fanconi Anemia, Jack and Lisa Nash underwent in-vitro fertilization followed by a procedure called pre-implantation genetic screening to choose an embryo that would have HLA proteins (B44, B35, A2, A26) that matched Molly, and to choose an embryo that would also be free of Fanconi anemia.

21. Ethics: This is the first example of the use of pre-implantation genetic screening to select for a baby solely as a treatment for its sibling. Question 7: Describe/Explain two ethical objections someone might have to allowing the Nashes to use this technique. Question 8: Describe/Explain two reasons why you think the Nashes should be allowed to use this technique. Question 9: What kind of regulations if any should be used for parents hiring doctors to do this procedure? When do YOU think it is OK to carry out this procedure? Pre-Implantation Genetic Screening

22. A3 A26 B41 B35 FANCC Normal A1 A2 B35 B44 FANCC Normal FANCC FANCC Select a Baby: HLA Match, Normal Mother Father A2 A26 B44 B35 Molly

23. A1 A2 B35 B44 FANCC Normal Question 10: Using your knowledge of how chromosomes segregate during meiosis, what percent of Mrs. Nash’s eggs would carry a normal chromosome 9 and a chromosome 6 with the A-2, B-44 alleles? No chance 25% 50% 75% 100%

24. A3 A26 B41 B35 FANCC Normal A1 A2 B35 B44 FANCC Normal Question 9: If the same percentage of Mr. Nash’s sperm carry the correct chromosome 9 (normal) and 6 (A26, B35), what is the probability that a single embryo would be a perfect HLA match for Molly and not develop Fanconi anemia? Explain your answer. 1/2 1/4 1/8 1/16 1/32 Father

25. A2 A2 A2 A2 A2 A2 A2 A2 A1 A1 A1 A1 A1 A1 A1 A1 A3 A3 A3 A3 A3 A3 A3 A3 A26 A26 A26 A26 A26 A26 A26 A26 FANCC FANCC FANCC FANCC FANCC FANCC FANCC FANCC B41 B41 B41 B41 B41 B41 B41 B41 B35 B35 B35 B35 B35 B35 B35 B35 B35 B35 B35 B35 B35 B35 B35 B35 B44 B44 B44 B44 B44 B44 B44 B44 Normal Normal Normal Normal Normal Normal Normal Normal A26 A26 FANCC FANCC FANCC FANCC FANCC FANCC FANCC FANCC Normal Normal Normal Normal Normal Normal Normal Normal B35 B35 A3 A3 B41 B41 A2 A1 A2 A1 B44 B35 B44 B35

26. Update on the Nashes After four in vitro fertilization attempts, Lisa Nash gave birth to a baby boy, Adam, on August 29, 2000. Adam’s placenta was gathered immediately and all the cord blood saved. Molly started chemotherapy to destroy her bone marrow and received a transfusion of the cord blood cells a month later. Today Molly, Adam, and new little sister Delaine are all doing well. The transplant cured Molly’s bone marrow failure, but she still suffers from Fanconi anemia and visitsthe doctors 35-40times a year to screen for solid-tumor cancers. A common cold could have dire consequences for her, but her bone marrow is functioning normally.