How should the end come?

A POINT OF VIEW

Longer life spans and changing attitudes towards care and hospital treatment mean attitudes towards dying and euthanasia are complicated, writes Katharine Whitehorn.

The Queen no longer sends telegrams to people on their 100th birthday - it's cards these days, and at the present rate it won't be long before she's just about keeping the Post Office in business.

Some of the people who reach that age - or even mere chicks of 80 and 90 - lead vigorous and fulfilling lives. But an awful lot don't, so it's small wonder that the question of how they should live comes up more and more.



Many long terminal illnesses are simply horrific, in spite of good hospices and living wills



Not surprising, either, that Mary Warnock, who had to wrestle with the issues of the start of life, embryos and all that, and Elizabeth Macdonald, a distinguished oncologist at Guy's Hospital in London, have turned their attention to how we should die. The question is how and if life should be brought to an end.

This summer they've been on the stump at literary festivals for their thoughtful and enlightened book Easeful Death, most recently at the Edinburgh Book Festival. There's been more than one bill defeated in Parliament that was designed to make it easier for a really awful life to be ended, but they think that, in spite of the difficulties, our views on human life generally have developed enough for one to succeed now.

It seems certain, anyway, since we can now thwart death in so many ways and live so long, that we're going to have to rethink the end of life the way we have, effectively, re-thought the beginning, what with contraceptives and abortions and IVF.

30-year sabbatical

We're only beginning to realise the implications of us all living so much longer. The Times letters page recently discussed whether Lloyd George's first old age pension in 1908 was or wasn't as generous in real terms as the state pension now, but the massive difference for the government bean-counters is, of course, the sheer length of time the thing has to be paid out.

Until relatively recently, people mostly only lived for a few years after stopping work - now they may easily hang on for another thirty or forty years. In the words of Dr Richard Nicholson, who edited a magazine called Medical Ethics, "a 30-year sabbatical is just not on".

If you're educated and have enough money, if you're obsessed by bridge or golf or grandchildren, if you're allowed to go on working, you may have a good time, at least until your health packs up.


And I suppose if you feel your life is utterly meaningless you can commit suicide - certainly more suicides among the old succeed, compared with the young, for whom it may sometimes be just a cry for help.

But along with the statistics about how long we're all going to live - in a dozen years or so half the population will be over 50 - comes the chilling projection that the very old can look forward to ten years of chronic illness.

Obviously, properly cared for, sick and disabled people can live worthwhile lives. But many long terminal illnesses are simply horrific, in spite of good hospices and "living wills".

Anyone my age has plenty of deaths to brood about. When my mother died, she was staying with friends, who brought her breakfast in bed and found that she had died in her sleep.

When I rang a cousin to tell her, she said: "Oh, how wonderful" - she had been a mental health nurse, and knew only too well the alternatives. I know that one relation of mine starved herself to death, a horrible way to go - so fed up was she with constant intractable pain in spite of really good care - it's a myth that all pain is controllable.

Miserable fragment

When we saw another relative in his nursing home the day before - mercifully, he died - we came away saying "if it was an animal you wouldn't let it go on".

Margaret Forster, in her compelling book Precious Lives discusses two deaths. One was a beloved sister-in-law, dying of cancer, with morphine enough to end her life had she wished, but she didn't and clung on to the last painful moment.

When it came to Margaret Forster's father, a robust, stalwart, highly independent man who had declined over the years to a miserable fragment of himself, she finished the book by saying that history would find it odd that we let him fade away in such a manner - the last words of the book are: "It is odd. It is wrong."


Incredibly telling, to me, is a phrase from the American philosophy Professor Sam Gorovitz whose book on medical ethics called, inevitably, Doctors' Dilemmas tells of a young man who begged the doctors to give his agonised, dying mother more morphine. He was told no, because it might suppress her breathing.

The man accepted this at first, but then came back and said: "Where is it written that the cancer has some right to be the cause of death? That the doctor's job is to keep the patient alive until the tumour can cash in its claim?"

Time was, when doctors were more paternalistic and much less likely to be sued, that a good doctor might quietly help a patient to go. They can still give massive doses of painkiller - if the intention is to relieve pain, not to end a life. It's known as the double effect.

But there are a dozen reasons, and the Harold Shipman case is only one, why they have to be incredibly cautious. Acute pain isn't always the main misery - it can be complete loss of function.

Several European countries have some form of assisted dying; but in spite of the optimism of Warnock and Macdonald I had always thought it wouldn't work here, because we're so inefficient - if we can't even ensure that a miserable old lady gets her disgustingly soiled sheets changed, if a hospital can try to send a very confused elderly woman with dementia back home with no-one to control her heart pills, as Ros Coward recently related in the Guardian, how could we ever be sure we'd get it right about whether a sick person really wanted to go?

Swift death

Warnock and Macdonald have hopes that the time has come for it, even so.

My father had an old pupil who was a marvellous medical missionary and married to another. In retirement they cycled on a two-seater bicycle to raise money for the hospital in South Africa where they had worked. They were finally getting too old for this, but on the day after their Golden Wedding celebrations they set off on the tandem for a last ride round the British Isles - and were knocked over by a lorry and killed outright.

Everyone wrung their hands and said how awful it was - but what could be better than a very swift death, together, without the long agony of one losing the other, of operations and care homes, hearing and sight gradually going wrong, pain only just controlled.

I used to have a sort of Hollywood vision of my deathbed. I would lie on my pillows, pale but brave, and forgive my enemies - on the grounds that nothing would infuriate them more. I know now that I'm more likely to be half senile in hospital, hung about with tubes and drips, confused and hurting.

It may be very difficult to form a law that might give me an easy death, but I just hope they manage it before it's my turn to go.

一小塊長期吃 黑巧克力降血壓

【聯合晚報╱編譯夏嘉玲/美聯社芝加哥三日電】 2007.07.04 03:00 pm

每天吃一小塊黑巧克力可降血壓，但，吃多了可不好。
報系資料照片
可可對健康的好處再增一項。德國一項研究發現，長期吃含可可的黑巧克力，只要非常少量就有降低血壓的功效。這也是首度發現黑巧克力只要吃一點點就能裨益健康。

這項研究呼應多項研究對含可可食物有益健康的結論。可可含植物性化合物黃烷醇 (flavanols)，喝紅酒有益心臟，也是拜這種成分所賜。

不過，巧克力熱量高，專家不鼓勵把大吃特吃當成降血壓的手段，免得體重上升，反而導致更多健康風險。

科隆大學研究人員讓44名56歲到73歲的受試對象吃德國Ritter Sport方塊型黑巧克力，每天吃一小塊，等於攝取6公克多黑巧克力，或者吃大小分量差不多但不含可可的白巧克力。受試者體重大致正常，但血壓略高或有前高血壓，研究開始時血壓平均為收縮壓147毫米汞柱，舒張壓86毫米汞柱。18周後，吃黑巧克力的人平均收縮壓下降近3毫米汞柱，舒張壓下降近2毫米汞柱。吃白巧克力的人則血壓幾無變化。

研究論文已發表在最新一期「美國醫學會期刊」。論文主要執筆者陶伯特博士指出，吃黑巧克力所降血壓幅度不大，但已足夠減少罹患心血管疾病風險，不過該研究並未就心血管疾病進行後續追蹤研究。研究人員為了避免受試者吃進太多熱量，把他們每天攝取的巧克力量限制為30卡。

研究人員指出，長期攝取黑巧克力可擴張血管，維持血壓穩定。美國約翰霍普金斯醫學院艾佩表示，最有效的非藥物降血壓方法還是保持體重正常與減少鹽分攝取，如果再經常吃少量黑巧克力，或許更能事半功倍。

【2007/07/04 聯合晚報】@ http://udn

山中伸彌

Public release date: 10-Aug-2006
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press

With few factors, adult cells take on character of embryonic stem cells
With the introduction of just four factors, researchers have successfully induced differentiated cells taken from mouse embryos or adult mice to behave like embryonic stem cells. The researchers reported their findings in an immediate early publication of the journal Cell.

The cells--which the researchers designate "induced pluripotent stem cells" (iPS)--exhibit the physical, growth, and genetic characteristics typical of embryonic stem cells, they reported. "Pluripotent" refers to the ability to differentiate into most other cell types.

"Human embryonic stem cells might be used to treat a host of diseases, such as Parkinson's disease, spinal cord injury, and diabetes," said Shinya Yamanaka of Kyoto University in Japan. "However, there are ethical difficulties regarding the use of human embryos, as well as the problem of tissue rejection following transplantation into patients."

Those problems could be circumvented if pluripotent cells could be obtained directly from the patients' own cells.

"We have demonstrated that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors," Yamanaka said. Fibroblasts make up structural fibers found in connective tissue.

Embryonic stem cells are derived from inner cells of the mammalian blastocyst, a ball of cells that develops after fertilization and goes on to form a developing embryo. Cells from other parts of the body can also be "reprogrammed" by transferring their nuclear contents into egg cell precursors called oocytes or by fusion with embryonic stem cells, earlier studies showed.

Those findings provided evidence that unfertilized eggs and embryonic stem cells contain factors that can confer pluripotency to differentiated cells, Yamanaka said.

"We hypothesized that the factors that play important roles in the maintenance of embryonic stem cell identity also play pivotal roles in the induction of pluripotency" in other body cells, he explained.

The researchers selected 24 genes--all previously found to play a role in early embryos and embryonic stem cell identity--as candidate factors that might give body cells the ability to become other cell types.

The researchers found that four of those factors, known as Oct3/4, Sox2, c-Myc, and Klf4, could lend differentiated fibroblast cells taken from embryonic or adult mice the pluripotency normally reserved for embryonic stem cells.

They further reported that transplantation of the iPS cells under the skin of mice resulted in tumors containing a variety of tissues representing the three primary types found in mammalian embryos. Those primary "germ layers" in embryos eventually give rise to all an animal's tissues and organs.

Following injection into blastocysts, iPS cells also contributed to mouse embryonic development.

"The finding is an important step in controlling pluripotency, which may eventually allow the creation of pluripotent cells directly from somatic cells of patients," Yamanaka said.

While the findings could have wide applications, stem cell experts caution that the study of embryonic stem cells has much further to go.

"We still do not know whether the four factors can generate pluripotent cells from human somatic cells," Yamanaka said. Use of c-Myc, a gene implicated in many human cancers, may not be suitable for clinical applications, they added, and the process may require specific culture environments. It also remains unclear whether iPS cells can do everything that embryonic stem cells can.


###
The researchers include Kazutoshi Takahashi of the Institute for Frontier Medical Sciences, Kyoto University in Kyoto, Japan and Shinya Yamanaka of the Institute for Frontier Medical Sciences, Kyoto University in Kyoto, Japan and CREST, Japan Science and Technology Agency in Kawaguchi, Japan.

This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan to S.Y. This work is also supported in part by the Takeda Science Foundation, the Osaka Cancer Research Foundation, the Inamori Foundation, the Mitsubishi Pharma Research Foundation, and the Sankyo Foundation of Life Science and by a Grant-in-Aid from the Japan Medical Association to S.Y. K.T. was supported by a fellowship from the Japan Society for the Promotion of Science.

Takahashi et al.: "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors" Publishing online August 10; Scheduled for the August 25, 2006 issue of Cell.

幹細胞(真的)來了

胚胎幹細胞的點石成金術
作者:Jun-An Chen
2007/06/08

幹細胞的魔術師們再度向世人展現不可思議的胚胎幹細胞點石成金術，這回他們把體細胞 ”返老還童”變成胚胎幹細胞了!

在生命科學研究的領域裡，大概很能再找到一個比“胚胎幹細胞”還要炙手可熱的話題。生物學家對胚胎幹細胞愛不釋手，因為到目前為止，沒有任何一種成體幹細胞能比胚胎幹細胞更具分化的全能性。生物學家目前已能利用各種適當的細胞訊息傳遞分子，在培養皿裡忠實地將胚胎幹細胞引導成為各種不同的體細胞 (像是運動神經元，多巴胺分泌神經元，肝臟細胞等)。這也是為何大家對於胚胎幹細胞寄予厚望，希望有朝一日胚胎幹細胞能完成治癒人類各種難纏的神經退化性疾病以及糖尿病的夢想。然而，相對於生物學家對胚胎幹細胞的愛不釋手，宗教人士卻對胚胎幹細胞的研究恨之入骨，因為要建立人類胚胎幹細胞株，首先必須先摧毀來自臨床使用剩餘的體外人工受精胚囊 (blastocyst)，然後再從內質團 （inner cell mass) 裡分離出幹細胞培養。雖然生物學家認為此時的胚囊尚未具有神經系統，根本稱不上是“胚胎”，但摧毀任何形式的授精卵，還是具有一定程度的道德爭議。因此，如何能在這場愛恨交加的掙扎裡尋覓一個平衡點，就成為當前研究以及使用胚胎幹細胞的一門重要課題。

2003年時，英國劍橋大學的 John Gurdon研究小組發現，如果將已完全分化的小鼠胸腺細胞注射至非洲爪蟾的卵母細胞時，卵母細胞的某種天然神奇配方會重新設定胸腺細胞並讓其開始表現胚胎幹細胞的特殊轉錄因子 - Oct4 (1)。這項突破性的研究開啟了胚胎幹細胞點石成金術的濫觴。2006年時，日本京都大學山中伸（Shinya Yamanaka) 教授的研究小組進一步解開這個神奇配方，根據他們的研究結果，只需要將四種基因 -Oct3/4, Sox2, c-Myc, Klf4- 送入已完全分化的纖維母細胞，即可以把纖維母細胞重新設定變回幹細胞。他們將這種 ”返老還童”的重新設定細胞稱之為”誘導式多能性幹細胞” (induced pluripotent stem cells, iPS cells) (2)。 iPS細胞的特質類似胚胎幹細胞，只要經由特殊訊號分子的引導，即可將它們轉換成為各種體細胞 (神經細胞或肝臟細胞)。更重要的是，移植到小鼠皮下組織的 iPS細胞也會導致畸胎瘤 (teratomas)，這也是胚胎幹細胞的一個重要特質。

許多幹細胞的研究學者對這項石破天驚的研究成果存著半信半疑的態度，畢竟四個轉錄因子就可以點石成金的確是太不可思議。然而，山中伸的研究小組在這星期又發表了第二代改良的 iPS細胞 (3)。第一代的 iPS細胞的基因甲基化程度與胚胎幹細胞有著顯著的差異。此外，第一代的 iPS細胞並沒有辦法和成鼠形成嵌合體 (chimera)。為了能更精確地將纖維母細胞完全的轉變成真正的胚胎幹細胞，他們這次還是使用原本的四個轉錄因子，但卻利用另一個特異表現在胚胎幹細胞裡的分子 -Nanog作為鑑定 iPS細胞的標記。另外，他們也在 Nanog載體後接上一段抗藥性基因，如此唯有真正被轉型成功的iPS細胞在加了抗生素的培養皿內才可以生存下來。利用這個改良方式所得到的第二代 iPS細胞不但俱有和胚胎幹細胞幾乎雷同的基因印痕 (imprinting) 模式，它們也可順利地和成鼠形成嵌合體並產生後代。這項結果顯示藉由體細胞 ”返老還童”的第二代 iPS細胞已經跟胚胎幹細胞幾乎是具有一模ㄧ樣的特質了!更令人興奮的是，另外兩個美國的實驗室也利用這四個相同的轉錄因子成功地將體細胞轉變成iPS細胞 (4-5)，他們的實驗數據也幾乎完全符合山中伸研究小組發表的結果。這些幹細胞魔術師已儼然成為貨真價實的胚胎幹細胞煉丹士!

筆者去年發表在 Sciscape的“幹細胞的魔術師 - 解開長生不老的轉錄迴圈”文末提到: 這三篇論文已初步地解開幹細胞”永保青春”的神祕面紗，接下來如何利用這個”幹細胞轉錄程式”讓其他體細胞可以”返老還童”變成幹細胞將是更大的挑戰。未來如果能比較癌症細胞，體細胞，與幹細胞在染色質和組蛋白間的協調有何異同，更能實質的為臨床醫學帶來莫大的貢獻。但筆者萬萬沒想到不到一年的光景，這樣的夢想就能完全實現!身為一位科學家，看到這樣的實驗結果固然異常興奮，但看著生物學者與上帝幾乎就是一步之遙時，不免感嘆: How far can we go?