Unit 4 What time do you go to school? 同步训练与答案_初中英语_中学数学网
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Unit&4&What&time&do&you&go&to&school?&同步训练与答案
作者：佚名 文章来源： 点击数： 更新时间： 22:45:09
教学内容］
一. Language Goals(目标)
1. Talk about routines. 谈论日常生活作息习惯。
2. Ask about and say time. 询问和表达时间。
二. Language structure(结构)
1. 行为动词的一般现在时。
2. 特殊疑问句,when和what time。
3. 关于频度副词always, usually, often, sometimes的使用。
三. Target Language. 目标语言。
1. What time do you get up?
I get up at six o’clock.
2. What time does he eat breakfast?
He eats breakfast at seven o’clock.
3. What time does she go to school?
She goes to school at eight o’clock.
4. When do people usually eat dinner?
People usually eat dinner in the evening.
5. What time is it?
It’s eight-thirty.
四. Key Phrases(重点词组)
△动词短语
get up 起床
get home到达家中
get to work到达工作岗位
make breakfast做早饭
make a shower schedule 做一个洗澡的安排
practice guitar 练吉它
leave home 离家
take a shower = have a shower 洗淋浴澡
take the Number 17 bus to the Santon Hotel
乘17路公共汽车去Santon 旅馆
go to class 上课
go to school 上学
go to work 上班(反义词 go home)
have breakfast/dinner/lunch 吃早、晚、午饭
go to bed 睡觉(反义词get up)
put on 穿衣服(反义词take off)
do one’s homework 做家庭作业
tell sb. about sth. 告诉某人某事
know about sth. 知道某方面的情况
love to do ＝ like to do 喜欢干某事
listen to the early morning news on radio
听电台早间新闻
watch the early morning news on TV
看电视早间新闻
△其他短语
around six o’clock 六点左右
in the morning 在早上
in the afternoon 在下午
in the evening 在晚上
listen to 听…
五. Key Points (疑难解析)
1. What time is it? It’s …
这是询问时间的惯用法,如：
A: Excuse me. What time is it, please?
请问几点了？
B: It’s nine o’clock. 九点了。
英语时间的表达
(1)整点时间可表示为“钟点数+o’clock”或直接读钟点数,省去o’clock。如：
It’s ten o’clock a. m. 现在是上午十点整。
(2)非整点时间可直接采取读数法。如：
It’s eight-thirty. 是八点三十分。
注意时间的表达方式：用数词。点与分钟之间用连字如：
eleven-thirty 十一点三十分
nine-twenty-five 九点二十五分
6:10 →six-ten 8:50→eight-fifty
9:30→nine-thirty 10:15→ten-fifteen
7:45→seven forty-five 11:05→eleven-five
(3)非整点时间的分钟数不超过30分钟,也可用介词“past”。如：
6:10→ten past six
11:05→five past eleven
10:15→ a quarter past ten或fifteen past ten
8:15→a quarter past eight或fifteen past eight
9:30→half past nine或thirty past nine
(4)非整点时间的分钟数超过30分钟,用介词to。如：
11:50→ten to twelve
7:31→twenty-nine to eight
9:45→a quarter to ten或fifteen to ten
12:59→one to thirteen
此句话还有几种表达方式。如：
What is the time? 几点了？
What time is it by your watch? 你的手表几点了？
用英语大声说出下列表格中的时间
A: What’s the time, please?
B: It’s twelve o’clock.
8:05 o five.
8:15 It’s eight fifteen.
8:25 twenty-five.
8:30 thirty.
It’s a quarter past eight.
twenty-five
8:35 thirth-five.
8:40 forty.
8:45 It’s eight forty-five.
8:50 fifty.
8:55 fifty-five.
OR twenty-five
It’s a quarter to nine
2. what time与when
what time翻译为“几点”问的是具体的时间,一般回答要具体到小时。
What time do you go to school?
你什么时候/几点上学？
I go to school at half past seven o’clock.
我七点半去上学。
回答具体到点钟,且注意在几点前边的介词用at。
when也是对时间的提问,但与what time的区别是：用when提问,回答既可以是具体的时间,也可以是不具体的时间,如：in the morning,last year,in 1998等范围大的时间,例如：When does he take a shower？他什么时候洗澡？
He takes a shower in the morning.
他在早上洗澡。
也可用具体时间：
I take a shower at 6 o’clock in the morning.
我早上六点洗澡。
例. 对下列划线部分提问,将句子变为特殊疑问句。
(1)It’s seven o’clock.
__________ __________ is it?
(2)He was born in 1992.
__________ was __________ born?
解析：本题主要考查when与what time如何询问时间。
答案：(1)What time (2)When, he
3. 关于一般现在时。(语法重点)
(1)一般现在时态的意义是：①表示现在的特征或状态。如：He is at home today. 他今天在家。②表示经常性、习惯性的动作。常和频率副词always, often, usually及every day等表示时间的短语连用。如：I go to school at 7:00 every day. 我每天7点钟去上学。③表示主语具备的性格或能力。如：She likes pears very much. 她非常喜欢梨子。They speak English. 他们讲英语。
(2)肯定陈述句：当主语是第一、二和第三人称复数时,谓语动词用原形。当主语是第三人称单数时,谓语动词用第三人称单数形式。例如：
①They stay at home on Sundays.
他们星期天呆在家。
②He does his homework in the evening.
他在晚上做作业。
(3)否定句：当主语是第一、二及第三人称复数时,否定句借助助动词do+not,当主语是第三人称单数时,否定句借用does+not,并将动词第三人称单数还原。例如：
①They don’t stay at home on Sundays.
他们星期天不呆在家里。
②He doesn’t do his homework in the evening.
他晚上不做作业。
(4)疑问句：当主语是第一、第二及第三人称复数时,疑问句在句首加Do。当主语是第三人称单数时,疑问句在句首加Does,并把谓语第三人称单数还原。例如：
①Do they stay at home on Sundays?
他们星期天呆在家吗？
②Does he do his homework in the evening?
他晚上做作业吗？
△以speak为例归纳动词do的各种句式：
肯定式 否定式
I speak English.
You speak English.
He/She/It speaks English.
We/You/They speak English. I do not (don’t) speak English.
You do not (don’t) speak English.
He/She/It does not (doesn’t) speak English.
We/You/They do not (don’t) speak English.
疑问式和简略答语
Do I speak English?
Yes, you do.
No, you do not (don’t).
Do we speak English?
Yes, we/you do.
No, we/you do not (don’t). Do you speak English?
Yes, I do.
No, I do not (don’t).
Do you speak English?
Yes, we do.
No, we do not(don’t). Does he/she/it speak English.
Yes, he/she/it does.
No, he/she/it does not (doesn’t).
Do they speak English?
Yes, they do.
No, they do not (don’t).
(1)We __________ (get up/gets up) at seven every morning.
(2)Jane __________ (don’t wake up/doesn’t wake up) at six every morning.
(3)My father often __________ (drink/drinks) lemonade for breakfast.
(4)____________(Does, Do)the girl often __________ (draw/draws)pictures in the park?
(5)My friend often __________ (come/comes) to school by bus.
(6)____________ (Does, Do) Sally and Ann often __________ (read/reads) English in class?
(7)Jim __________ (doesn’t do/doesn’t) his homework after supper every day.
(8)Jone __________ (go/goes) home at 4:00 in the afternoon.
答案：(1)get up (2)doesn’t wake up (3)drinks
(4)Does, draw (5)comes (6)Do, read
(7)doesn’t do (8)goes
解析：本题考查一般现在时的各种句型。
(1)主语是we,与谓语动词原形搭配。
(2)考查否定句,由于主语是第三人称单数,助动词应相应变化。
(3)主语是第三人称单数。
(4)行为动词是一般现在时的疑问句,主语the girl是第三人称单数,助动词应选相应的Does,后面的动词则用原形,选draw。
(5)此题与(3)题考点相同,选comes。
(6)此题与(4)小题考点一样,但主语Sally and Ann相当于they,不是单数,答案为Do, read。
(7)此题较难,不能丢了第二个do,它是主语的动词译为“做”,答案为doesn’t do。
(8)考点与(3)、(5)相同。
4. always, usually, often 和sometimes
这四个副词表示行动或动作的频率。频率最高的是always(总是),其次是usually(通常,总是),often(经常,时常),sometimes(有时),使用时要注意它们在句中的位置。由于频率副词表示的是经常性的、一般性的动作或情况,不是具体指某一次,因此常常和一般现在时连用,常位于行为动词前面,其他动词(指be动词、情态动词和助动词)的后面。本单元重点学习usually“通常”。
如：When do you usually get up?
你通常什么时候起床？
I usually get up at six o’clock.
我通常六点起床。
What time does your sister usually get up?
你妹妹通常什么时候起床？
She usually gets up at 6:30.
她通常6：30起床。
5. 在本单元中,出现了大量的动词短语,我们通过下面的题目来巩固一下。
填空完成短文,注意词形变化。
Scott works very ___1___ (长时间地). He usually ___2___ (起床) at 17:00. He ___3___ (洗澡)and ___4___ (做早饭). What a funny time to make breakfast! ___5___ (早饭后), he practices his guitar, then he ___6___ (穿上)his jacket and ___7___(上班). ___8___ (为了到达工作岗位). He ___9___ (乘17路公汽) to the Santon Hotel. The bus usually leaves at 9:15. He works ___10___ (通宵). People love ___11___ (听他说话)! He ___12___ (到家)at 7:00 and watches the early morning news on TV. He ___13___ (睡觉) at 8:30, a tired but happy man. Can you think what his job is?
解析：这篇短文是本单元67页上的阅读文章,出现了不少习惯用语,同学们一定要大声反复诵读直到脱口而出,增加语感,品味出词语在具体语境中的用法,从而将知识和能力融合为一体,举一反三,灵活运用。另外,一般现在时第三人称单数形式仍然是难点,不少同学,一看就会,一听就懂。可是一开口、一动手就错,什么原因呢？就是练习少了,用中国的思维方式学英语,解决这个问题的惟一办法就是行动起来,参与交际活动,反复应用,脱口而出。学地道的英语,不是一味地背语法条款。
答案：(1)long hours (复数)
(2)gets up (第三人称单数)
(3)takes/has a shower(第三人称单数)
(4)makes (his) breakfast
(5)After breakfast(表示时间的介词短语)
(6)puts on
(7)goes to work
(8)To get to work (动词不定式)
(9)takes the Number 17 bus
(10)all night
(11)to listen to him (动词不定式)
(12)gets home
(13)goes to bed
6. What a funny time to make breakfast! 多么可笑的做早饭的时间啊!
这是一个以what开头的感叹句,不是特殊疑问句。
△感叹句用来表示感情的喜、怒、哀、乐等,其结构为感叹词(what, how)+强调成分+主语+动词等。what用来强调句中的名词,how用来强调句中的形容词、副词或动词。例如：
What a fine day it is today! 今天天气多好啊!
What interesting books they are! 多有趣的书啊!
How beautiful the garden is! 这个花园多美呀!
例. It is an interesting movie. (将句子变为以what和how开头的感叹句,句意相近)
(1)_________ _________ _________ movie it is!
(2)_________ interesting the movie is!
解析：本题考查感叹句的结构。
答案：(1)What an interesting
7. listen to, hear和sound
△listen to意为“注意听”,表示有意识地去听,但不一定听得见什么,强调听的动作。(listen不及物,listen to及物)如：
They are listening to the teacher. 他们在听老师说。
△hear意为“听见”,表示耳朵里听到了,但不一定有意识地听,强调听的结果。如：
I’m sorry to hear that.
听到那个消息我很难过。
△sound意为“听起来,听上去”,可作连系动词,后接形容词作表语,还可以和like连用。例如：
The music sounds sweet. 这音乐听起来悦耳。
例. 用hear, listen to, sound填空。
(1)Be quiet! (安静)_________ _________ the actor. I can’t _________ him.
(2)Let’s play basketball.
That _________ good.
解析：(1)句意：安静!听演员说。我听不见他的话。第一个“听”强调听的过程。第二个听强调听的结果(听不见)。
(2)句意：我们打篮球吧!听上去不错。
答案：(1)Listen, to, hear
8. To get to work, he takes the number 17 bus to the Saite Hotel.
为了赶去上班,他要乘坐去赛特宾馆的17路公共汽车。
(1)to get to work 是动词不定式作目的状语。
(2)take a bus 表示“乘坐公共汽车”。如：
I get to school at 8:15. 我八点一刻到达学校。
9. Thanks for your letter. 谢谢你的来信。
Thanks for… 谢谢……,其后接名词,或相当于名词的词。如：
Thanks for your help. 多谢你的帮忙。
Thanks for coming to see me. 谢谢来看我。
10. I usually get up at around six fifteen.
我通常在大约六点一刻时起床。
around 表示“大约”的意思。
around 还可表示“在周围,在附近”,“朝……四处”。
如：There are around 100 people in the hall.
大厅里大约有一百人。
She looks around the room. 她环顾一下室内。
11. School starts at nine o’clock.
九点钟学校开始上课。
start动词,表示“开始”的意思,相当于begin。
开始做某事
如：What time does the party start? 聚会几点开始？
It starts to rain (raining). 开始下雨了。
He usually starts studying at eight at home.
他在家通常8点开始学习。
六. 知识点巩固
1. He is always the last one _________ to school.
A. goes B. to go C. go D. to goes
2. He _________ up at 7:00 and _________ the early morning news on TV.
A. gets, sees B. gets, watchs
C. gets, watches D. gets, to watches
3. Here are your pants. _________!
A. Put them on B. Put on them
C. Put it on D. Put on it
4. Tony usually gets up _________ 5 o’clock.
A. in B. at C. on D. about
5. Lucy, can you _________ me about your school?
A. talk B. tell C. speak D. know
6. Do you want to know _________ my morning?
A. about B. at C. around D. for
7. What time _________ she _________?
A. do, go to bed B. does, goes to bed
C. does, go to the bed D. does, go to bed
8. Do you like _________ music?
A. hear B. to hear C. to listen to D. listen to
9. ―What time do you usually go to bed?
―At half _________ ten.
A. at B. on C. past D. in
10. ―_________ do you like dogs?
―Because they are smart(聪明的).
A. What B. What…for C. Why D. When
Keys: 1. B 2. C 3. A 4. B 5. B 6. A 7. D 8. C 9. C 10. C
【模拟试题】(答题时间：90分钟)
I. 用下列字母组成单词
1. oershw ___________ 2. bysu ___________
3. artst ___________ 4. ftera ___________
5. oetlh ___________ 6. busrh ___________
II. 用英语表达下列短语
1. 回家 ___________ 2. 上学 ___________
3. 洗澡 ___________ 4. 在大约五点钟 ___________
5. 去上班 ___________ 6. 看早间新闻 ___________
7. 做家庭作业___________ 8. 去睡觉 ___________
9. 练习弹吉他 ___________ 10. 乘坐公共汽车 ___________
III. 请画掉每句中多余的一个词,并将正确的句子写在横线上
1. What time isn’t is it?
___________________________________________________
2. What time does she they usually get up?
__________________________________________________
3. What when time does he play volleyball?
___________________________________________________
4. We play plays basketball at eight o’clock.
___________________________________________________
5. It’s thirty one o’clock.
____________________________________________________
IV. 试着用英语表达下列时间。
1. 7:20 2. 8:30 3. 9:18 4. 10:58
5. 11:46 6. 14:40 7. 4:32 8. 5:50
9. 6:16 10. 8:50
V. 单项选择
1. He doesn’t like ___________ late.
A. be B. to C. is D. to be
2. The student has ___________ to do every day.
A. some homeworks B. a lot of homework
C. much homeworks D. many homework
3. My mother goes to work ___________.
A. by her bike B. on her bike
C. by a bike D. on bike
4. We have ___________ supper late in the evening.
A. a B. an C. one D. /
5. What time ___________ Jim ___________ games?
A. does, play B. is, playing
C. do, play D. are, playing
6. Can you ___________ “window” in English?
A. talk B. tell C. spell D. speak
7. People have ___________ in the middle of the day.
A. breakfast B. lunch
C. supper D. dinner
8. Chinese people like ___________ CCTV news at 7:00 pm.
A. looking B. reading
C. seeing D. watching
9. It’s six now. Lanlan ___________ up, but she often ___________ up at half past six.
A. gets, is get B. gets, is getting
C. is getting, gets D. gets, gets
10. I often do some reading, but ___________ I like to watch TV.
A. sometime B. some time
C. some times D. sometimes
11. ―___________ does he want to eat?
―Noodles.
A. What B. How C. Why D. When
12. She is ___________ CCTV news with her parents.
A. looking B. reading C. watching D. seeing
13. Jeff ___________ the bus to school.
A. goes B. brings C. gets D. takes
14. Tina often goes to ___________ work after ___________ breakfast.
A. the, the B. /, / C. /, the D. the, a
15. ___________ interesting movie it is!
A. What an B. What C. How D. How an
16. Please look ___________ the book and listen ___________ me.
A. at, at B. for, on C. with, at D. at, to
17. ―What ___________ do you usually go to the music club?
―I usually go there ___________ around 7:30.
A. day, to B. time, at C. date, in D. time, on
18. ―___________？
―It’s nine o’clock.
A. What day is it B. What’s the time
C. What’s the date D. When is it
19. ___________ Lucy and Lily want to go to the park?
A. Do B. Does C. Is D. Are
20. Mr. Wang goes to work early ___________ the morning.
A. in B. at C. on D. of
21. ―Lucy, _________ your coat, please.
―It’s time to go to school.
A. put on B. put off
C. look after D. look like
22. What time is ___________?
A. that B. this C. it D. the clock
23. Alice often takes the number 11 bus ___________ the hotel.
A. in B. to C. at D. for
24. Mike is English, ___________ he likes Beijing Opera.
A. or B. and C. also D. but
25. The students stay ___________ home ___________ Sundays.
A. at, at B. on, at C. at, on D. on, on
VI. 选择对话补全句子,有两个选项是多余的
A: Hi, Lucy! ____1____?
B: Well, I live near my school, so I get up at a quarter to seven. I never go to school late.
A: Do you have breakfast at home?
B: Yes, ____2____.
A: When do you go to school?
B: ____3____, so I go to school at seven forty-five.
A: ____4____?
B: I leave school at five past five and ____5____.
a. What time do you usually get up on weekdays
b. I usually have some cakes and a glass of milk
c. Class begins at eight o’clock
d. I get home at five-thirty
e. When do you play games
f. I have lunch at school
g. When do you get home
VII. 完形填空
What do you do at the weekend? Some people like to ___1___ at home, but others like to go ___2___ a walk or play football. Mr Jack works hard in factory during the ___3___. At the weekend, he always ___4___ the same thing. On Saturday he ___5___ his car and on ___6___ he goes with his family to a village by car. His uncle and aunt have a farm there. It isn’t a ___7___ one, but there is always ___8___ work to do on the farm. The children help with the animals and give them their ___9___. Jack and his wife help in the fields. At the end of the day, they are all ___10___ and Jack’s aunt gives a big meals.
1. ( ) A. work B. sit C. stay D. play
2. ( ) A. out B. for C. to D. away
3. ( ) A. day B. evening C. night D. weekdays
4. ( ) A. does B. has C. goes D. plays
5. ( ) A. sweeps B. driving C. sells D. washes
6. ( ) A. Monday B. Sunday C. Saturday D. Wednesday
7. ( ) A. small B. big C. far D. long
8. ( ) A. much B. many C. little D. few
9. ( ) A. clothes B. drinks C. food D. water
10. ( ) A. early B. late C. hungry D. full
VIII. 阅读理解,根据短文内容补全句子
Most children like watching TV. It’s very interesting. By watching TV they can see and learn a lot and know many things about their country and the world. Of course, they can also learn on the radio. But they can learn better and more easily on TV. Why? Because they can hear and watch at the same time. But they can’t see anything over the radio. TV helps to open children’s eyes. TV helps to open their brains(大脑), too. They can learn newer and better ways of doing things. They may find the world is now smaller than before. Many children watch TV on Saturday or Sunday evening. They are always busy with their lessons. But a few children watch TV every night. They go to bed very late. They can’t have a good rest. That’s too bad.
1. Children ______the programs on TV.
2. They can get to know the world by __________ TV.
3. They like TV programs __________ than radio programs.
4. They can learn more easily when they can hear and watch at the __________ time.
5. There are some teaching programs on the __________, too.
6. TV helps to __________ children’s eyes and their brains.
7. That’s the new __________ of working out the problem.
8. With TVs and radios around us, the world is getting __________.
9. Children can’t watch TV for too long because they are always __________ with their lessons.
10. It is __________ for children to watch TV every night.
IX. 单词拼写
A)根据句意及首字母提示补全单词。
1. Liu Xiang is a r________ star.
2. I usually eat b________ at seven in the m________.
3. Weiwei g________ to school at eight o’clock.
4. My mother is very b________ today. She can’t come to see me.
5. We make a s________ schedule.
6. My brother likes to sleep a little l________ in the morning.
7. What t________ do you u________ go to school?
8. She wants to j________ the chess club.
9. My f________ color is red.
10. Can you p________ the violin?
B)根据句意,用括号内所给词的正确形式填空。
1. Uncle John likes ________ (make) things.
2. We can ________ (swim) now.
3. Why am I the last one? B ________ I am the ________ (old).
4. Rich has two ________ (brother).
5. My brother can take a ________ (show).
X. 根据图示写出Zhao Ming的一日活动。要求每图写一个句子。
1._____________ 2. _____________ 3. _____________
4. _____________ 5. _____________ 6. ____________
7. ______________ 8. _____________
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　　网友评论：（只显示最新10条。评论内容只代表网友观点，与本站立场无关！）Is It Possible to Control Cancer Without Killing It? - The New Yorker
An experimental new drug can make some leukemic cells mature into healthier ones.
Illustration by Brian Stauffer
For almost thirty years, William Kuhens worked on Staten Island as a basketball referee for the Catholic Youth Organization and other amateur leagues. At seventy, he was physically fit, taking part in twenty games a month. But in July of 2013 he began to lose weigh his wife told him he looked pale. He saw his doctor, and tests revealed that his blood contained below-normal numbers of platelets and red a these are critical for, respectively, preventing bleeding, supplying oxygen, and combatting infection. Kuhens was sent to the Memorial Sloan Kettering Cancer Center, in Manhattan, to meet with Eytan Stein, an expert in blood disorders. Stein found that as much as fifteen per cent of Kuhens’s bone marrow was made up of primitive, cancerous blood cells. “Mr. Kuhens was on the cusp of leukemia,” Stein told me recently. “It seemed that his disease was rapidly advancing.” Leukemia is a disorder of the blood cells, which form in the bone marrow. For reasons not always clear to scientists, immature cells fail to develop properly into mature ones and instead continue to multiply, crowding out normal blood cells. Patients are at risk of massive bleeding and sepsis, a severe complication of infection. There are many kinds of leukemia, depending on the type of blood cell involved and the pace at which the cancer advances. Kuhens was developing acute myelogenous leukemia, or A.M.L., which is estimated to occur annually in at least fifty thousand people worldwide, most of them adults, a fewer than a quarter of patients survive for more than five years. Kuhens knew that his prognosis was grim, likely measured in months. Stein treated him with four courses of chemotherapy, to no significant effect. The only options were experimental. Stein had sent a sample of Kuhens’s bone marrow to be analyzed for the presence of thirty or so gene mutations that are known to be associated with blood cancers. The tests revealed one notable mutation, in a gene that produces an enzyme called IDH-2. Normally, the enzyme helps to break down nutrients and generate energy for cells. When mutated, it creates a molecule that alters the cells’ genetic programming. Instead of maturing, the cells remain primitive, proliferate wildly, and wreak havoc. About fifteen per cent of all A.M.L. patients carry the mutated enzyme. In recent months, Stein had been participating in a Phase 1 clinical trial of a drug, AG-221, d the drug was developed by the pharmaceutical company Agios. Phase 1 studies represent the very first tests of
they are mainly meant to assess a new drug’s safety, with little expectation that the treatment will help. Of the first ten patients who had been treated, three had died from their disease before the drug’s effects could be evaluated. But the data on six of the seven remaining patients were striking: five had gone into complete remission and one entered a partial remission. (The other patient did not improve, and his leukemia continued to grow.) Stein described one patient to me, a woman in her late sixties with A.M.L. She had already undergone a bone-marrow transplant, had relapsed, and then h nothing helped. To Stein’s surprise, after three months on AG-221, her leukemia had gone into complete remission and her blood count had returned to normal. “It was transformative,” Stein said. “She gained weight and told me that the pep in her step was back.” Another patient, a sixty-year-old man with A.M.L., also had failed to benefit from several regimens of chemotherapy, and he, too, went into remission after taking AG-221. Moreover, the side effects of the medication, which is given orally, have been manageable—mostly mild nausea and a loss of appetite. This past spring, Kuhens entered the drug trial and received his first dose. Within weeks, the leukemic-cell count in his bone marrow had fallen from fifteen per cent to four per cent, and his counts of healthy blood cel he has been in complete remission for four months. The most noticeable side effect has been a metallic taste in his mouth. “For some reason, I can’t stand mayonnaise,” Kuhens told me recently. He just celebrated his fiftieth wedding anniversary. “I want to be around for a while,” he said, “and I don’t know how long this drug will last.” In April, Stein presented his findings to a packed auditorium at the annual meeting of the American Association for Cancer Research, in San Diego. It was the first public airing of the results of AG-221; patients with progressive A.M.L. had never improved so quickly and definitively. I received the news with tempered excitement. In the nineteen-seventies, when I trained in internal medicine, and later in hematology and oncology, acute myelogenous leukemia was the cancer to beat. The disease typically overwhelms its victims, relegating them to the intensive-care unit, where they require intravenous antibiotics, blood transfusions, and, as their lungs and heart fail, support on ventilators. The most effective initial treatment was, and still is, a pair of highly toxic chemotherapy drugs, daunorubicin (or sometimes a related one, adriamycin) and cytarabine. The side effects are profound: the first family of drugs causes arrhythmias and heart-muscle damage, often leadin the second drug is toxic to the central nervous system, particularly the cerebellum, resulting in severe lack of balance and co?rdination. Combined, the two agents might kill the leukemic cells in the marrow, but they also kill healthy blood cells, causing patients to enter a limbo with an “empty marrow,” during which we doctors used to pray that their normal cells would regrow. Daunorubicin and adriamycin have a distinctive red color, and in my day medical interns referred to them as “the red death,” because most of the patients who took them ultimately died of their disease. In response, my mentors argued that “desperate diseases require desperate measures.” By comparison, Stein’s results were breathtaking. Still, his trial hadn’t involved many patients, and they hadn’t been followed for long. Cancer is wily, and some drugs that target mutations can show benefits that soon evaporate as the tumor adapts. In June, however, at the European Hematology Association conference, in Milan, Stéphane de Botton, a hematologist at the Institut Gustave Roussy, near Paris, presented updated results that were equally promising. The findings covered thirty-five patients, most of them with A.M.L. Ten had died within a month of entering the trial, from complications related to the disease. But fourteen patients had improved on AG-221, including nine whose leukemia went into complete remission. Five were stable
in six, the leukemia continued to grow. The patients also experienced few side effects, de Botton told me recently, and some patients have been in remission for more than six months. “These data signal the first real advance for A.M.L. in thirty years,” Stephen Nimer, the director of the Sylvester Comprehensive Cancer Center, at the University of Miami, and an eminent leukemia researcher and clinician, told me. “It’s a huge step forward.” The breakthrough is notable in part for the unconventional manner in which the drug attacks its target. There are many kinds of cancer, but treatments have typically combatted them in one way only: by attempting to destroy the cancerous cells. Surgery aims to remove the entire
chemotherapy drugs are toxic radiation generates toxic molecules that break up the cancer cells’ DNA and proteins, causing their demise. A more recent approach, immunotherapy, co?pts the body’s immune system into attacking and eradicating the tumor. The Agios drug, instead of killing the leukemic cells—immature blood cells gone haywire—coaxes them into maturing into functioning blood cells. Cancerous cells traditionally have been viewed as a lost cause, fit only for destruction. The emerging research on A.M.L. suggests that at least some cancer cells might be redeemable: they still carry their original programming and can be pressed back onto a pathway to health. Most cancers, once they spread, are incurable. Cancer researchers are desperate to raise the number of patients who go into remission, to prolong those remissions, and to ultimately prevent relapse. So when a new way of attacking cancer comes along, it is often greeted with incautious euphoria and an assumption that the new paradigm can be quickly converted into a cure for all cancers. In 1971, President Nixon announced the War on Cancer, based on the mounting belief, born of research in the nineteen-sixties, that cancer is caused by viruses. As it turns out, although viruses often cause cancer in lower animals, they do so less frequently in humans. In 1989, Harold Varmus and Michael Bishop won the Nobel Prize for their discovery, thirteen years earlier, that normal genes could mutate into cancer-causing oncogenes, which appear to drive the unchecked growth and behavior of malignant cells. Cancer was now seen as a genetic disease, and in some cases, such as familial breast cancer, genetic tests were developed that could indicate whether an individual was at high risk for the malignancy. Advances in DNA technology and in computing led to the mapping of the healthy human genome, and of other genomes, including those of various cancers. Scientists assumed that they would soon decipher how tumors arise and find a way to stop them. In the case of some cancers, that promise has been fulfilled, but for most, especially once they have spread, it has not. In 1998, after the development of new drugs that could shut down certain cancers by choking off their blood supply—an advance, known as anti-angiogenesis, that has given rise to the drug Avastin—the Nobel laureate James Watson predicted that this work would “cure cancer in two years.” Immunotherapy has recently been shown to be highly effective against melanoma and kidney cancer, but many other cancers manage to evade this type of therapy. The more scientists learn about cancer, the more diverse and vexing their opponent appears. Most cancers have several potential ways of developing. Even within a single tumor, individual cancer cells may follow separate road maps. A drug designed to target one pathway may succeed in destroying only a fraction of the tumor, leaving the rest to grow, spread, and kill. The IDH-2 mutation is just one of many enzyme mutations that are found in acute myelogenous leukemia. Recently, Timothy Ley, a researcher at Washington University, in St. Louis, and an expert on the genetics of blood cancers, published a study involving two hundred patients with A.M.L.; he found that each patient harbored a unique set of mutations. “It’s complex, but I’m not daunted,” Ley told me. “At least now we know what we’re dealing with.” Agios hopes that AG-221 will become a key in treating those cancers which are driven by IDH-2. In March, the company launched clinical trials of another drug, AG-120, which targets a different mutated enzyme, IDH-1. The mutation occurs in as many as ten per cent of A.M.L. patients, but it’s also found in seventy per cent of patients with a type of brain tumor called a glioma and in fifty per cent of cases of cancer of the cartilage. The treatment of cancer, which traditionally adopted a destroy-the-village strategy, is becoming ever more like precision warfare. “We treat people with the specific mutation who may benefit,” David Schenkein, the C.E.O. of Agios, told me. “We don’t treat people who would not respond to the drug.” One day in July, I visited the Agios laboratory, not far from the M.I.T. campus, in Cambridge, Massachusetts. Precision medicine has been made possible in part by advances in computer technology, enabling scientists to depict enzymes, receptors, and other key cellular molecules in exquisite, three-dimensional detail. Pharmaceutical companies like Agios have large databases that keep track of known drugs and their physical contours. Finding or creating a drug for a cancer-causing molecule can be a matter of deciphering the molecule’s shape and determining what sort of drug would best match it, like fitting a key to a lock. AG-221 came to exist in much this manner. For several years, scientists had been aware that some patients with acute myelogenous leukemia carry the mutated IDH-2 enzyme. The healthy enzyme helps the cell generate energy by breaking down a molecule called isocitrate, leaving another, called alpha-ketoglutarate, as a by-product. In 2009, Agios researchers discovered that the mutated enzyme leaves a different by-product, a molecule called 2-hydroxyglutarate, or 2-HG, which appears to switch off certain genes in the cell nucleus. As a result, the cell fails to mature into a fully functioning blood cell and instead multiplies dangerously. An Agios team soon devised AG-221, which binds to the abnormal enzyme and prevents it from creating 2-HG. The researchers were nonetheless surprised when the malignant cells matured into healthy ones. As it turns out, a cell containing the mutated IDH-2 enzyme also still contain the healthy one functions correctly, but its benefits to the cell are swamped by the effects of the aberrant enzyme. Once the mutant enzyme is neutralized, the healthy one puts the cell back on track. In effect, the leukemic cell harbors the genetic progra the drug allows the program to be accessed and enables the cancer to grow up. At Agios, a bioanalytical chemist named Kelly Marsh showed me how the drug works. In a large laboratory space, Marsh and her colleagues were preparing to test the efficacy of a second-generation version of AG-221. She sat at a lab bench with a plastic tray the s it had ninety-six wells, each containing a few drops of clear liquid—suspensions of leukemic cells with the IDH-2 mutation. Some of the wells had been treated with increasi others were untreated, to serve as controls. Marsh’s analysis would show how effective the drug was at neutralizing the errant enzyme. The most prominent object on the lab bench was a mass spectrometer—a machine about the size of a steamer trunk, with fine plastic tubing emanating from it. Marsh lined up the plastic tray so that an automated pipette drew up about a tenth of a drop from each of the wells and sent it through the tubing and into the machine. Within the spectrometer, the liquid would be heated into a gas and passed through a powerful electric field, where its mass could be calculated to several decimal points and its molecular makeup could be determined. A computer readout indicated how much 2-HG, the by-product of the aberrant enzyme, remained in each well. Marsh would have to run the test scores of times before she had sufficient data to draw statistically valid conclusions. Still, the results from this run were easy to grasp. As the dose of the drug was increased, the amount of 2-HG fell, in some cases as much as ninety per cent. The leukemic cells had been neutralized, as they had been in the clinical study of patients like William Kuhens. “It’ll have to be your place. I Airbnb’d myself out of my apartment tonight.”
That afternoon, I examined microscope images of the bone marrow of a patient who had not been treated with the drug. As a hematologist, I often dread taking in this view. Up close, healthy marrow looks like an Impressionist painting—a variegated landscape of cell types and colors. Leukemic marrow is a monotonous ca the images I was looking at showed hardly any normal blood cells being made. Then I examined images from a patient who had received the Agios drug. Typically, when a patient with A.M.L. is treated with high doses of chemotherapy, the marrow is emptied what’s left is a moonscape of fat globules and fibrous tissue. The images at Agios showed robust marrow: the leukemic cells had been forced to mature and had reverted to functioning white blood cells, red blood cells, and platelets. They were transformed. I had seen something similar only once before. The first scientific paper I ever wrote, some thirty-five years ago, was about an unusual blood cancer called acute promyelocytic leukemia, or A.P.L. My paper noted that patients typically died from massive hemorrhage and that even after intensive chemotherapy their remissions lasted only a year or so. In the nineteen-eighties, the disease became a curiosity for scientists, because of a new drug that was being employed against it, one whose effects mirror those of AG-221. The drug, called all-trans-retinoic acid, or ATRA, causes leukemic cells to abandon their relentless growth and to mature into white blood cells. ATRA and AG-221 attack different molecules in their respective cancers: AG-221 targets an enzyme that, when not mutated, is essential to the cell’ ATRA attacks a hybrid protein—the result of chromosomes breaking and faultily recombining—that should not otherwise exist. Nonetheless, when ATRA came into use, it was the first time that a cancer had been neutralized by forcing its cells to mature. The slides I saw of marrow from patients treated with AG-221 looked a great deal like the slides I’d seen from patients with acute promyelocytic leukemia who had been treated with ATRA. The principle was the same: cancer cells could be made healthier again. The idea for ATRA grew out of research by Zhen-yi Wang and Zhu Chen, of the Ruijin Hospital, in Shanghai. They were studying acute promyelocytic leukemia and wondered whether there was another way to treat the cancerous cells besides killing them. Wang was inspired by a passage from the Analects of Confucius: “If you use laws to direct the people, and punishments to control them, they will merely try to evade the punishments, and will have no sense of shame. But if by virtue you guide them, and by the rites you control them, there will be a sense of shame and of right.” Wang later wrote, “If cancer cells are considered elements with ‘bad’ social behavior in our body, ‘educating’ rather than killing these elements might represent a much better solution.” Wang and Chen were aware of work by Leo Sachs, a researcher at the Weizmann Institute of Science, in Israel, who had found that some leukemic cells seemed to have retained their ability to mature into healthy cells, at least in laboratory experiments. For a treatment agent, the Chinese scientists turned to all-trans-retinoic acid, a derivative of Vitamin A, which in Shanghai had just been approved to treat skin diseases such as psoriasis and acne. When the researchers exposed leukemic cells to ATRA, they appeared to mature, released from their primitive state. In 1985, Wang treated his first patient with ATRA: a five-year-old girl with acute promyelocytic leukemia who had not improved with chemotherapy and was dying. Within a week of treatment, she had begun to improve, and by three weeks she “miraculously went into complete remission,” Wang and Chen wrote in 2008, in the journal Blood. The authors noted that she was now twenty-six years old and healthy. In 1988, the Shanghai Institute of Hematology had published the results of a study in which twenty-four patients were given ATRA: twenty-three entered a complete remission, their leukemic cells having matured. This success was soon confirmed by other hematologists across the globe. But researchers discovered that the benefits of the drug often were not lasting. The leukemic cells, reprogrammed to mature and behave, exhibited a strong tendency to become cancerous again within three to six months. Chen, drawing on the work of researchers at Harbin Medical University, in northeastern China, experimented with arsenic trioxide as a follow-up agent. (Arsenic compounds were an active ingredient in an anticancer remedy popular among local healers.) It seemed that arsenic trioxide caused mature blood cells to commit suicide, a process called apoptosis. The resulting treatment was a one-two punch: ATRA triggered the leukemic cells to mature, whereupon they became vulnerable to the second drug, which destroyed them. Three decades ago, the remission rate for acute promyelocytic leukemia was forty per cent. Today, with the combination therapy, it is ninety-five per cent, and most of those patients are cured. The effectiveness of ATRA was long viewed as an anomaly, but today researchers working on AG-221 and acute myelogenous leukemia often cite it as an inspiration. “A.M.L. is a disease that we all fear,” Harold Varmus, who has followed the ATRA research for years, told me. “There were findings in the laboratory suggesting that leukemia cells could differentiate, and it is gratifying to see this approach moving into the patient setting.” The critical question is how long the benefits of AG-221 will last. “The issue is durability,” Martin Tallman, the chief of the Leukemia Service at the Memorial Sloan Kettering Cancer Center and a professor at Weill Cornell Medical College, told me. “Some patients have been in remission for six to eight months. But, based on prior studies in acute leukemia, the concern is that these people may ultimately relapse.” Tallman believes that the next step in treatment should involve combining AG-221 with a chemotherapy drug, as well as with other targeted inhibitors of gene mutations, or with bone-marrow transplantation. One potential virtue of highly targeted drugs is that their side effects are far less severe than those of traditional chemotherapy drugs. “No major toxicity with AG-221 has been observed so far,” Tallman said. “And it seems that, as you increase the dose, patients go into remission more quickly.” In medical school, we were taught that although cancer comes in many forms, it has one immutable characteristic: it is composed of immature cells. The research on these blood cancers, however, suggests that this trait may be reversible after all, and that the cancer cells, when prompted to mature, become susceptible to therapies to which they would otherwise remain resistant. Blood cancers are a fairly small subset of cancers as a whole. Recently, scientists working with solid tumors of the lung, ovaries, and pancreas have had success in forcing those cancer cells to mature into something like normalcy. These achievements have sprung from research not on metabolism but on stem cells. In the early nineteen-sixties, the Canadian biologists James Till and Ernest McCulloch showed that, in mice, all blood cells originate from primitive, undifferentiated cells in the bone marrow. These blood-forming stem cells are rare—perhaps one in a hundred thousand cells—and are unremarkable when seen under the microscope: small, bland, and round, offering no indication of their marvellous capacity to reconstitute the entirety of our blood system. Scientists have since shown that many of our body tissues also arise from sp there are neural stem cells in the brain, intestinal stem cells in the gut, and cardiac stem cells in the heart. Researchers are now investigating what triggers these cells to differentiate and develop into our various tissues, and to what extent those instructions can be manipulated. In 1994, John Dick, now a professor at the Princess Margaret Cancer Center and at the University of Toronto, posited that cancer, too, might originate from its own particular stem cell. Dick’s work was highly controversial, but subsequent researchers have reported evidence of stem cells in breast cancer, colon cancer, and melanoma, as well as in cancers of the prostate, the lung, and the pancreas. The definitions can be unclear. To some scientists, the leukemic cells in A.M.L. inclu to others, they are simply immature blood cells. And not everyone sees the same value in the research. “I understand full well the attractiveness and the seduction of the cancer-stem-cell model,” William Kaelin, a cancer biologist at Harvard’s Dana-Farber Cancer Institute, told me. “But so far it hasn’t made any predictions that I wouldn’t have otherwise made. I think we already knew that cancers tended to co?pt stem-cell pathways that are important for normal stem cells. And I think we already knew that many genes that are involved with stem-cell biology were occasionally mutated in cancers.” Nonetheless, investors and drug companies have leaped at the notion of cancer stem cells. Robert Weinberg, a prominent cancer researcher at M.I.T., recently co-founded a company called Verastem, while Regeneron, an established biotech company, added cancer stem cells to its research portfolio. In 2004, scientists at the University of Michigan and the University of Texas joined the molecular biologist Larry Lasky and a lawyer, Robert Gavin, to start OncoMed, which is investing heavily in cancer-stem-cell research. The company has five drugs in early-phase clinical trials, under the direction of the oncologist Jakob D some six hundred mil and potential funding of more than five billion dollars, should its milestones be met, from pharmaceutical giants like Bayer, GlaxoSmithKline, and Celgene. Whether or not cancer stem cells actually exist, the search for them has highlighted at least one useful insight, involving a mutation in a gene that plays a key role in prompting stem cells to mature. The mutation was discovered in 1917, by Thomas Hunt Morgan, an American biologist who revealed the importance of chromosomes in heredity. Much of Morgan’s work was performed at Columbia University, where he studied mutations in Drosophila melanogaster, the common fruit fly. Morgan found that a certain gene, when mutated, produced a cleft in the fly’s wing. The gene, called Notch, has turned out to be critical in the development of mammalian embryos, including humans, helping to make sure, for instance, that our blood vessels are patterned correctly. But when the gene is mutated it can become overly active and prevent the cell that contains it from reaching maturation. In 2008, OncoMed began a clinical trial of an experimental drug. Like AG-221, it was designed for a distinct subset of patients, in this case those whose cancers carry a mutated form of the Notch gene. The drug effectively dampens the overactive gene, enabling cells to mature. One of the first patients was a woman her tumors had metastasized and could not be cured by surgery, and she had undergone a dozen treatment regimens, including chemotherapy. All failed. But the anti-Notch drug stopped the cancer, after a fashion: her tumors did not shrink, which in oncology is the classical criterion for response, but neither did they grow. Her cancer seemed to have entered a kind of equilibrium, as if frozen or paralyzed. This arrest in its growth lasted for more than five hundred days. But the effects eventually waned, the cancer regrew, and she died of the malignancy. So far, the trial has included fifty- more than a third of them have shown a similar response. Cancers of the pancreas, lung, and ovary have been paralyzed for a hundred days or more. Further research has found that targeting the Notch mutation in these three cancers can prompt the cells to mature and more closely resemble normal tissue cells. I studied microscope images of some of those cancers. Before the anti-Notch therapy, the malignant cells of a pancreatic tumor were primitive and aggressive in appearance, with large nuclei, and multiplying profusely. After treatment, the changes were striking: the cancer cells resembled mature pancreatic tissue. The Notch blocker “pushed the cells down the differentiation cascade,” John Lewicki, the chief scientist at OncoMed, told me. “What we’ve largely observed in all our pre-clinical work to date is that when you block these pathways you largely get stable disease. To me, that’s not surprising, because we’re not necessarily killing cells.” In recent clinical trials, the Notch blocker has been given to patients in conjunction with chemotherapy. “When you combine these agents, you change the stem cells’ fate,” Lewicki said. “You not only differentiate them but you make them much more susceptible to the impact of chemotherapy.” This spring, I spoke with Gerald Wildes, a sixty-seven-year-old former truck designer in Tennessee. In November of 2011, he developed pancreatic cancer a he was also treated with radiation and chemotherapy. About a month later, the cancer showed up in his lungs. Wildes entered the Notch study in combination with chemotherapy. “The way I understand it, this treatment is supposed to get to the intelligence of the tumor,” Wildes said. “At the time, I was probably the first primate in Tennessee—something above a hog, anyway—to jump into the program.” During his first fifteen months of treatment, he experienced no new growths of cancer, and the tumors in his lungs shrank slightly. Since then, the benefits have faded, but Wildes told me that he was grateful for the quality time he gained. In October of last year, Usha Malik, a forty-six-year-old homemaker in New York City, learned that she had pancreatic cancer that had spread to her liver. Surgery was not an option. She saw Eileen O’Reilly, a pancreatic-cancer researcher at the Memorial Sloan-Kettering Cancer Center, and O’Reilly got her into the experimental trial. “It was a tough decision,” Malik told me. “I have a daughter who is twenty-two years old. My husband needs me and my daughter needs me.” Malik received the anti-Notch drug along with standard chemotherapy. The treatment regimen gave her nausea and diarrhea and left her exhausted. But the tumors in her liver nearly disappeared, and the mass in her pancreas became markedly smaller. “I was back driving, trying to do everyday work,” Malik said. The benefit was sustained for six months, until a CT scan revealed that one of her tumors had grown slightly. O’Reilly noted that the survival rate for pancreatic-cancer patients like Malik, whose disease has spread to the liver, is typically no more than several months. “Pancreatic cancer is a disease where new approaches are keenly needed,” O’Reilly said. “This experimental drug appears to get at, at least theoretically, one of the fundamental issues of cancer resistance to treatment.” OncoMed is planning to test the Notch-blocking approach by comparing the results of treatment using a combination of standard chemotherapy and the Notch drug with the outcome of treatments based on standard chemotherapy alone. Cancer does not have one fatal flaw. It advances along many paths, sometimes incrementally, often unpredictably, like the science arrayed against it. Nonetheless, these latest findings offer an unanticipated opportunity for scientists to re?xamine what many of us took for granted: that cancer cells must be destroyed if the patient is to improve. These discoveries could enable researchers to target cancers that were previously beyond treatment. For patients, they offer evidence that it is possible to live longer, and better, with cancer—and they provide hope that scientists are advancing on a cure. ? Sign up for the daily newsletter.Sign up for the daily newsletter: the best of The New Yorker every day.
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