Can we reprogram adult cells into eggs?

 

By Sophie Balmer, PhD

 

Oogenesis is the female process necessary to create eggs ready for fertilization. Reproducing these keys steps in culture constitutes a major advance in developmental biology. Last week, a scientific group from Japan amazingly succeeded and published their results in the journal Nature. They replicated the entire cycle of oogenesis in vitro starting from adult skin cells. Upon fertilization of these in vitro eggs and transfer in adult females, they even obtained pups that grew normally to adulthood providing new platforms for the study of developmental biology.

 

Gamete precursor cells first appear early during embryonic development and are called primordial germ cells. These precursors then migrate to the gonads where they will remodel their genome via two rounds of meiosis to produce either mature oocytes or sperm depending on the sex of the embryo. For oocyte maturation, these two cycles occur at different times: the first one before or shortly after birth and the second one at puberty. The second round of meiosis is incomplete and the oocytes remain blocked in metaphase until fertilization by male gametes. This final event initiates the process of embryonic development, therefore closing the cycle of life.

 

Up until last week, parts of this life cycle were reproducible in culture. For years, scientists have known how to collect and culture embryos, fertilize them and transfer them to adult females to initiate gestation. This process called in vitro fertilization (IVF) has successfully been applied to humans and has revolutionized the life of millions of individuals suffering specific infertility issues and allowing them to have babies. However only a subset of infertility problems can be solved by IVF.

Additionally, in 2012, the same Japanese group recreated another part of the female gamete development: Dr. Hayashi and colleagues generated mouse primordial germ cells in vitro that once transplanted in female embryos recapitulated oogenesis. Both embryonic stem (ES) cells or induced pluripotent stem (iPS) cells were used for such procedure. ES cells can be derived from embryos before their implantation in the uterus and iPS cells are derived by reprogramming of adult cells. Finally, a couple of months ago, another group also reported being able to transform primordial germ cells collected from mouse embryos into mature oocytes.

 

However, replicating the full cycle of oogenesis from pluripotent cell lines in a single procedure constitutes an unprecedented discovery. To achieve this, they proceeded in different steps: first, they produced primordial germ cells in vitro from either skin cells (following their de-differentiation into iPS cells) or directly from ES cells. Second, they produced primary oocytes in a specific in vitro environment called “reconstituted ovaries”. Third, they induced maturation of oocyte up until their arrest in meiosis II. This process took approximately the same time as it would take in the female mouse and it is impressive to see how the in vivo and in vitro oocytes are indistinguishable. Of course, this culture system also produced a lot of non-viable eggs and only few make it through the whole process. For example, during the first step of directed differentiation, over half of the oocytes contain chromosome mispairing during meiosis I, which is about 10 times more than in vivo. Additionally, only 30% complete meiosis I as shown by the exclusion of the 1st polar body. However, analysis of other parameters such as the methylation pattern of several genes showed that maternal imprinting was almost complete and that most of the mature oocytes had normal number of chromosomes. Transcription profiling also showed very high similarities between in vitro and in vivo oocytes.

The in vitro oocytes were then used for IVF and transplanted into mouse. Amazingly, some of them developed into pups that were viable, grew up to be fertile and had normal life expectancy without apparent abnormalities. However, the efficiency of such technique is very low as only 3.5% of embryos transplanted were born (compare to over 60% in the case of routine IVF procedures). Embryos that did not go through the end of the pregnancy showed delayed development at various stages, highlighting that there are probably conditions that could be improved for the oocytes to lead to more viable embryos.

Looking at the entire process, the rate of success to obtain eggs ready for transplant is around 7-14% depending on the starting cell line population. Considering how much time these cells spend in culture, this rate seems reasonably good. However, as mentioned above only few develop to birth. Nonetheless, this work constitutes major advancement in the field of developmental biology and will allow researchers to look in greater detail at the entire process of oogenesis and fertilization without worrying about the number of animals needed. We can also expect that, as with every protocol, it will be fine-tuned in the near future. It is already very impressive that the protocol led to viable pups from 6 different cell line populations.

 

Besides its potential for increasing knowledge in the oogenesis process, the impact of such research might reach beyond the scope of developmental biology. Not surprisingly, these results came with their share of concerns that soon this protocol would be used for humans. How amazing would it be for women who cannot use IVF to use their skin cells and allow them to have babies? Years ago, when IVF was introduced to the world, most people thought that “test-tube” babies were a bad idea. Today, it is used as a routine treatment for infertility problems. However, there is a humongous difference between extracting male and female gametes and engineering them. I do not believe that this protocol will be used on humans any time soon because it requires too many manipulations that we still have no idea how to control. Nonetheless, in theory, this possibility could be attractive. Also, for the most sceptic ones, one of the major reason why this protocol is not adaptable to human right now is that we cannot generate human “reconstituted ovaries”. This step is key for mouse oocytes to grow in vitro and necessitate to collect the gonadal somatic cells in embryos which is impossible in humans. So, until another research group manages to produce somatic gonadal cells from iPS cells, no need to start freaking out 😉

 

 

STAP細胞:ちょっと話が上手すぎる?

 

By Sally Burn. PhD

Translated to Japanese by Jun Seita, M.D., Ph.D.

For the original post in English, click here.

2週間前、私たちは日本の理研・発生・再生科学総合研究センターの科学者が発表した、画期的なSTAP(刺激惹起性多能性獲得)細胞についてレポートしました。STAP細胞は、特定の機能に特化した分化細胞に物理的なストレスを与えることにより作成されます。これにより細胞は未分化で多能性をもった状態へとリプログラム(初期化)され、リプログラムされた細胞は胎児組織だけでなく胎盤などの胎児外組織の両方に分化することが示されました。この発見は、Nature誌に2報[1,2]セットになった論文として発表され、科学界に興奮と驚愕を巻き起こしました。患者特異的再生医療などへの応用の可能性は興奮を、その仕組みの驚くほどの簡単さは驚愕をもたらしたのです。実験で主に用いられた外部刺激とは酸でした。成熟した細胞を酸にさらすだけでリプログラミングが始まるのです。様々な反応の中で最も好意的なものは「ほんとにそんな簡単に出来るの?」でした。一方、数多くの著名な科学者含む多くの人々は懐疑的なコメントを浴びせかけました。

 

論文の発表から今日までに様々なことが起こりました。理研は論文の正当性に付いて公式な調査を始め、インターネット上では人々が再現実験の試みを報告し合い、また人々のリクエストに応じてNatureは論文を誰もが無料で読めるようにしました。状況をまとめると、様々なブログによって指摘されたNature論文2報と、同じく著者、小保方博士による2011年の論文における複数の疑義に対して理研は反応をみせました。この疑義は大きく2種類に分けられます。1つは本来別々の実験結果を説明する別々の図表で、同じ画像が使い回されている問題です。もう一つは、他の研究室では結果を再現できないという問題です。理研が現在調査しているのは最初の方の疑義に関してであり、(うっかりミスとして)説明できる可能性があります。もう一つの疑義は実際には理研の調査の対象となっていませんが、多くのニュースは、あたかも論文に発表された実験に不備があったため理研が調査している、と報道しています。

 

これらの一連の出来事の良い側面は実際とてもエキサイティングです。まず、だれもがアクセスできるブログの仕組みを使って、実験を再現しようとする科学者がデータと結果を共有しようとする動きが発生しました。次に、人々からの、論文を誰もが無料で読めるようにしてほしい、という要望をNatureは受け入れました。しかし一方負の側面は苦々しいものです。もしかしたら私が見たり聞いたりした身近な範囲に集中しているだけかもしれませんが、魔女狩りのような雰囲気がはっきりと存在しています。人々の意見が興奮から「ほら言わんこっちゃない」へと悪化するのはあっという間でした。STAPの再現性を問うブログのコメント欄はあら探しであふれています。あるブログは、STAP論文のデータを信じるかどうかの科学的な意義には乏しい一般投票を行っていて、現時点では64%の人が否定的と感じています。

 

ここで白状すると、私は小保方博士が潔白であることを主観的判断と知りながら願っています。私は、30歳の彼女が理研で自分の研究室を持っている?!、ということを知って大興奮しました。彼女が絶え間ない批判と疑義に向かい合いながら研究を続けて行くことの困難さを語ったインタビューを読みました。誰も彼女の発見が本当だとは信じないため、彼女は何度も実験を繰り返し、対照の種類を増やし、証拠を積み上げて行ったと書いてありました。結果としてNatureへの最初の投稿から採択まで5年の歳月を要したそうです。そして査読チームはついに論文を受理し、彼女の仕事は認められたのです!小保方博士は一夜にして科学界全体のスターとなり、STAP細胞の名は世界に轟いたのです。彼女は「非常に成功した若い女性の独立した科学者」という私の新しいロールモデルとなりました。この中で一番重要なのは「女性で独立した科学者」という点です。今日、独立した科学者になることは極めて難しいのです。生命科学分野における大学院生とポスドクの総数は2、30年前と比べて猛烈に増えています。しかし、終身雇用の独立した科学者のポストの数は増えていません。更に、そのレベルでは男性が数的に女性を圧倒しています(以前のすばらしい議論はこちら)。そのため、理系に進もうと考えている女性にとって、具体的なロールモデルはなかなか見つかりません。なので、主観的なバイアスだと指摘される恥を恐れずに言いますが、私は小保方博士が潔白であることを強く願っています。

 

一方、もし小保方博士の研究内容に間違えがあることが判明したら、それは理系の女性達の期待に満ちたロールモデルを失うことを意味します。それはまた一般の人々の「科学的プロセス」という概念への評価を毀損するでしょう。調査がおこなわれていることは、大手メディアが盛んにつたえています。一般の人々は反射的に、科学研究の規律は乱れ、このような事案がしょっちゅうあると考えるようになるでしょう。なんといってもNatureはもっとも評価の高い有名な科学誌の一つなのですから。研究費を拠出する立場の人々の反応はさらに重大な損害をもたらすかもしれません。だから我々は対策を講じなければなりません。実際の科学的不正の件数を減らすだけでなく、不正を働く動機の発生自体に対して。

 

Natureは最上級の科学誌で投稿された論文には厳しい査読が行われます。小保方博士は何年にも渡って疑念と向き合い、自説を強化するための実験を重ねてきたと言っていました。他にできることはなかったのでしょうか?一つは著者たちの責任である、うっかりミスによる画像の重複利用です。これは絶対に起こってはなりません。特に研究者人生を賭けて既成概念を覆すような論文をNatureに投稿する時には。しかし実際には起こります、とくに成功か失敗かの賭けが巨大な時には。一般の人々は知らないかもしれませんが、科学実験を実行するのは完璧なロボットではありません。通常、疲れた、超過労働なのに低賃金の大学院生やポスドクです。彼らは人間で、眠気を覚ますためのブラックコーヒーとセミナーで提供されるピザを燃料に活動しています。彼らにも家があり家庭がありますが、16時間以上帰れないなんてざらです。彼らはミスります。私もミスります。読者のあなたもミスったことがあるでしょう。そしてそういうミスはプレッシャーを受けている時に特に起きやすいのです(ポスターの締め切りまで1時間とか、真夜中にこっそりと新しく思いついた実験に取り組む時とか)。ミスを防ぐにはどうしたいいのでしょうか?これはそう簡単ではありません。根を詰めすぎたり、些細な問題に頭が囚われたりといった科学者の性格によるところはあるかもしれません。しかし、「論文出版か破滅か」の圧力を少し弱めて、働く環境を改善することは確実に効果があるでしょう。論文を出さなければならないことへのプレッシャーはしばしばデータの改ざんも引き起こします。データが出なければ論文は出ず、研究者キャリアに別れを告げることになるからです。

 

もし今回の画像の重複利用が本当にうっかりミスだというなら、透明性について議論されるべきです。理研は調査しているという事実を公表するべきだったのでしょうか?公表したことによってマスコミは蜂の巣をつついたような騒ぎになり、偽造があったので調査することになったと一般の人々に知らしめました。もし調査の結果、すべての疑いが晴れたとしても、小保方博士は今後ずっと偽造の疑いで告発されたという烙印をしょっていくことになります。しかし、この点を考慮しても、私は「公表するべき」だと考えます。科学における不正行為の調査は絶対に公表されるべきです。ここ10年の、誰もが論文を読むことが出来るというオープンアクセスへの動きは、科学をより多くの人のものへと前進させました。私たちは科学の透明性を上げるために出来るだけのことをするべきです。

 

実際に、この調査は科学をさらにオープンアクセスにする鍵となる出来事になるかもしれません。実際、STAP論文が発表されて以降、とっても面白いことが起こっています。ブログでは世界中の科学者が「うわさによればとっても簡単な酸によるリプログラミング」を再現しようとした経験を議論しています(具体的にはPubPeer[3,4]とPaul Knoepfler’s blogを参照してください)。このようなオープンな議論はいままでほとんどありませんでした。現時点で2つのSTAP論文のPubPeerのページは27000回以上閲覧されています。TwitterもSTAPに関する活発な意見交換の場になっているし、RedditにはSTAP論文の責任著者であるCharles Vacantiの研究室の技官を名乗る人物が登場し実験方法の議論が続いています。

 

いまのところ10件の試みが公開されていますが、誰も小保方博士の結果を再現できた人はいません。Natureは公式な調査はまだ開始していないようですが、興味深いことに、独自に聞き取り調査を行った模様です。「Nature news編集部の質問に回答した10人の有名な幹細胞科学者のうち、一人も再現には成功していない」と報じています。これらは必ずしもオリジナルのデータが偽造であったことを示すものではありません。理想的には、科学的事実はつねに再現可能であるはずですが、しばしばそうは上手く行きません。すごい実験結果が出たと思ったら特定のロットの培地でしか成功しなかったり、動物実験の結果が飲み水・食べ物・ストレスに左右されたり、ということはみんな経験しているはずです。科学は、一般の人々がそうあるべきと思う様な、完全無欠の論理的怪物ではないのです。もし20回実験していつも上手く行っていたのに、新しいロットの培地に変わったとたん失敗する様になったとき、あなたは全てのデータを捨ててやり直しますか?理想の解答は「やりなおす」ですが、論文を出すことのプレッシャーの元で、たいがいはそうしません。そのデータを使って論文を書きます。そうでなければ研究者キャリアの破滅が・・・

 

もしかしたら、小保方研究室だけにあって、他では正確に真似ることの出来ないなにかがあるのかもしれません(悪名高き彼女の幸運の亀のペットが居ないとダメとか?)。ほとんどの再現実験では、STAP論文とは違う細胞に刺激を加えています。さらに、彼女の手法は「シンプル」といわれていますが、それらは彼女が何年もかけて磨き上げたものです。実際に、共著者の若山博士は、小保方研究室のある理研では再現できましたが、理研を離れてからはSTAP細胞を再現できていません。理想的には外部の科学者が小保方研究室に行き、彼女のトレーニングを受けて彼女の研究室の設備と試薬を使って再現実験をするべきでしょう。

 

この事件で一つ良かったことは、STAP再現性ブログを主催するPaul Knoepfler教授がtwitterを使ってNatureに、STAP論文を誰でも読めるオープンアクセスにするように呼びかけたことです。(Natureの論文を読むには通常研究所単位か論文ごとに高額の購読料を払う必要があります)。Natureは呼びかけに同意して今では世界中の誰もがSTAP論文を無料で自分自身で読むことが出来ます。これはオープンアクセスの流れの勝利です。STAP細胞の再現をめざす人々からの更なるリクエストは、小保方博士たちが詳細な手法を公開することですが、これはまだ実現していません。現実には小保方博士はなにもコメントを発表していません。とはいうものの、多くの人は見落としているかもしれませんが、彼女はうっかりミスによる画像の重複利用の可能性、についてだけ調査されているのが事実です。私は本当に彼女があらゆる疑いから潔白であることを願っています。なぜなら、そうでなければ彼女のキャリアはもちろん、一般からの科学に対する認識が大きく傷つくからだけではなく、彼女の発見自体が驚異的に素晴らしく画期的だからです。映画『X-Files』の台詞を借りれば「私は信じたい」です。

Leafing through the Literature

Thalyana Smith-Vikos

Highlighting recently published articles in molecular biology, genetics, and other hot topics

Can I get some of your gut bacteria?

While there have been many reports popping up in the literature that demonstrate a connection between gut microbiome and diet, Ridaura et al. have elegantly showed how the mammalian microbiome affects diet in a specific yet alterable manner that can be transmitted across individuals. The researchers transplanted fecal microbiota from adult murine female twins (one obsess, one lean) into mice fed diets of varying levels of saturated fats, fruits and vegetables. Body and fat mass did depend on fecal bacterial composition. Strikingly, mice that had been given the obese twin’s microbiota did not develop an increase in body mass or obesity-related phenotypes when situated next to mice that had been given the lean twin’s microbiota. The researchers saw that, for certain diets, there was a transmission of specific bacteria from the lean mouse to the obese mouse’s microbiota.

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In vivo reprogramming

Abad et al. have performed reprogramming of adult cells into induced pluripotent stem cells (iPSCs) in vivo. By activating the transcription factor cocktail of Oct4, Sox2, Klf4 and c-Myc in mice, the researchers observed teratomas forming in multiple organs, and the pluripotency marker NANOG was expressed in the stomach, intestine, pancreas and kidney. Hematopoietic cells were also de-differentiated via bone marrow transplantation. Additionally, the iPSCs generated in vivo were more similar to embryonic stem cells than in vitro iPSCs by comparing transcriptomes. The authors also report that in vivo iPSCs display totipotency features.

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Connection between pluripotency and embryonic development

Lee and colleagues have discovered that some of the same pluripotency factors (Nanog, Oct4/Pou5f1 and SoxB1) are also required for the transition from maternal to zygotic gene activation in early development. Using zebrafish as a model, the authors identified several hundred genes that are activated during this transition period, which is required for gastrulation and removal of maternal mRNAs in the zebrafish embryo. In fact, nanog, sox19b and pou5f1 were the top translated transcription factors prior to this transition, and a triple knockdown prevented embryonic development, as well as the activation of many zygotic genes. One of the genes that failed to activate was miR-430, which the authors have previously shown is required for the maternal to zygotic transition. Thus, Nanog, Oct4 and SoxB1 induce the maternal to zygotic transition by activating miR-430.

 

A microRNA promotes sugar stability

Pederson and colleagues report that a C. elegans microRNA, miR-79, targets two factors critical for proteoglycan biosynthesis, namely a chondroitin synthesis and a uridine 5′-diphosphate-sugar transporter. Loss-of-function mir-79 mutants display neurodevelopmental abnormalities due to altered expression of these biosynthesis factors. The researchers discovered that this dysregulation of the two miR-79 targets leads to a disruption of neuronal migration through the glypican pathway, identifying the crucial impact of this conserved microRNA on proteoglycan homeostasis.

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Establishing heterochromatin in Drosophila

It is known that RNAi and heterochromatin factor HP1 are required for organizing heterochromatin structures and silencing transposons in S. pombe. Gu and Elgin built on this information by studying loss of function mutants and shRNA lines of genes of interest in an animal model, Drosophila, during early and late development. The Piwi protein (involved in piRNA function) appeared to only be required in early embryonic stages for silencing chromatin in somatic cells.  Loss of Piwi leads to decreased HP1a, and the authors concluded that Piwi targets HP1a when heterochromatin structures are first established, but this targeting does not continue in later cell divisions. However, HP1a was required for primary assembly of heterochromatin structures and maintenance during subsequent cell divisions.

 

The glutamate receptor has a role in Alzheimer’s

Um and colleagues conducted a screen of transmembrane postsynaptic density proteins that might be able to couple amyloid-β oligomers (Aβo) bound by cellular prion protein (PrPC) with Fyn kinase, which disrupts synapses and triggers Alzheimer’s when activated by Aβo-PrPC . The researchers found that only the metabotropic glutamate receptor, mGluR5, allowed Aβo-PrPC  to activate intracellular Fyn. They further showed a physical interaction between PrPC and mGluR5, and that Fyn is found in complex with mGluR5. In Xenopus oocytes and neurons, Aβo-PrPC caused an increase in intracellular calcium dependent on mGluR5. Further, the Aβo-PrPC-mGluR5 complex resulted in dendritic spine loss. As a possible therapeutic, an mGluR5 antagonist given to a mouse model of inherited Alzheimer’s reversed the loss in synapse density and recovered learning and memory loss.

 

Keep playing those video games!

Anguera et al. investigated whether multitasking abilities can be improved in aging individuals, as these skills have become increasingly necessary in today’s world. The scientists developed a video game called NeuroRacer to test multitasking performance on individuals aged 20 to 79, and they observed that there is an initial decline in this ability with age. However, by playing a version of NeuroRacer in a multitasking training mode, individuals aged 60-85 achieved levels higher than that of 20-year-olds who had not used the training mode, and these successes persisted over the course of 6 months. This training in older adults improved cognitive control, attention and memory, and the enhancement in multitasking was still apparent 6 months later. The results from playing this video game indicate that the cognitive control system in the brains of aging individuals can be improved with simple training.

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Grow Your Own

Sally Burn

Imagine the scene: one of your descendants, sometime in the near future, in the aftermath of a particularly grisly altercation between their finger and a carving knife. Sans finger they dash over to the medicine cabinet, pop open a new tube of SOCK (Sox2, Oct4, c-Myc, Klf4. Copyright me, pharmaceutical companies of the future), rub it into the wound, and then wait for a new finger to grow. The finger is regenerated at its natural location from their own cells and is thus readily accepted by their body. Science fiction? Possibly, but a novel technique published this month in Nature may have laid the foundations to start exploring such regenerative therapies.

 

Maria Abad and colleagues, in the lab of Manuel Serrano in Madrid, have developed a method to reprogram adult cells into iPS (induced Pluripotent Stem) cells within a living mouse. These cells then differentiated in vivo into a number of tissue types, all without the need for any invasive or surgical action. To achieve this they took advantage of the cocktail of factors known to dedifferentiate adult cells into iPS cells: Oct4, Sox2, Klf4, and c-Myc. This combination was shown in 2007 to induce reprograming to a pluripotent state, acting like a “reset” switch. Over the last few years many research groups have taken advantage of this finding to create iPS cells from a variety of adult cell types in the lab. Experiments have also been conducted to show that the resulting iPS cells can then be differentiated into distinct tissue types both in a petri dish and when transplanted into animals. However, until now iPS cells have never been generated in vivo and then differentiated into tissues in their natural environment. The Madrid team generated transgenic mice in which expression of the genes encoding each reprograming factor can be induced using the antibiotic doxycycline. By transiently giving mice doxycycline they could turn on the genes and provide the animal’s own cells with the cues to become iPS cells.

 

The positive side of what happened next is that differentiated adult cells were indeed “reset” to become iPS cells. Moreover, at the transcriptome level these in vivo iPS cells were actually closer to ES cells than iPS cells generated in vitro and had features of totipotency. The in vivo iPS cells then went on to differentiate into a range of tissues. So far so good. However, the tissues they formed were within teratomas – a type of tumor containing multiple tissues that, whilst normal, are not supposed to be located in that part of the body. The teratomas occurred in multiple organs and contained tissues derived from all three embryonic germ layers, demonstrating that the in vivo iPS cells are pluripotent.

 

As you might expect the mice died fairly rapidly due to their tumors (within 6-10 weeks on one treatment protocol). There is therefore a lot of fine-tuning that needs to be done before such a technique could be used in humans. Firstly, a method to localize the reprograming to a specific organ or area will need to be developed. Moreover, we will need a way to control exactly which specialized cell types the iPS cells then differentiate into. A third issue is that the mice in this study were transgenic, with production of the four reprograming factors induced by doxycycline from artificially inserted transgenes. Genetically engineering humans is obviously rife with scientific and ethical hurdles. So another requirement is to find a way to produce the reprograming factors in the human body without the need for genetic modifications. This could conceivably be achieved by exogenously supplying the factors in the form of an injection or topical cream. Finally, the technique would need to be refined so that tumors don’t develop even at the treated site. These are pretty huge problems to address. However, this initial study has demonstrated that regenerative medicine may be more feasible than previously thought, by showing that in vivo reprograming is indeed possible.

 

Chromosome Silencing Offers New Insights into Down Syndrome

Sally Burn

Down syndrome is caused by the most common chromosomal abnormality in live-born humans: Trisomy 21. Individuals with Down syndrome have three copies (trisomy) of chromosome 21 instead of the usual two. This excess of genetic information leads to deviations in embryonic development such that the baby is born with a subset of defects from a spectrum of characteristic traits. The most obvious indicators are the distinctive Down syndrome facial features (almond shaped eyes, small ears, large tongue) and abnormalities of the hands (single crease on palm, small curved pinky fingers). Further examination may then reveal more serious medical problems including heart abnormalities, gastrointestinal defects, and impaired vision and hearing. Intellectual disabilities are also a common problem. Continue reading “Chromosome Silencing Offers New Insights into Down Syndrome”