Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com
We use prompt engineering to guide ChatGPT in the automation of text mining of metal–organic framework (MOF) synthesis conditions from diverse formats and styles of the scientific literature. This effectively mitigates ChatGPT’s tendency to hallucinate information, an issue that previously made the use of large language models (LLMs) in scientific fields challenging. Our approach involves the development of a workflow implementing three different processes for text mining, programmed by ChatGPT itself. All of them enable parsing, searching, filtering, classification, summarization, and data unification with different trade-offs among labor, speed, and accuracy. We deploy this system to extract 26 257 distinct synthesis parameters pertaining to approximately 800 MOFs sourced from peer-reviewed research articles. This process incorporates our ChemPrompt Engineering strategy to instruct ChatGPT in text mining, resulting in impressive precision, recall, and F1 scores of 90–99%. Furthermore, with the data set built by text mining, we constructed a machine-learning model with over 87% accuracy in predicting MOF experimental crystallization outcomes and preliminarily identifying important factors in MOF crystallization. We also developed a reliable data-grounded MOF chatbot to answer questions about chemical reactions and synthesis procedures. Given that the process of using ChatGPT reliably mines and tabulates diverse MOF synthesis information in a unified format while using only narrative language requiring no coding expertise, we anticipate that our ChatGPT Chemistry Assistant will be very useful across various other chemistry subdisciplines.
This publication is licensed for personal use by The American Chemical Society.
Concluding Remarks
Our research has successfully demonstrated the potential of LLMs, particularly GPT models, in the domain of chemistry research. We presented a ChatGPT Chemistry Assistant that includes three different but connected approaches to text mining with ChemPrompt Engineering: Process 3 is capable of conducting search and filtration, Processes 2 and 3 classify synthesis paragraphs, and Processes 1, 2, and 3 are capable of summarizing synthesis conditions into structured data sets. Enhanced by three fundamental principles of prompt engineering specific to chemistry text processing, coupled with the interactive prompt refinement strategy, the ChatGPT-based assistant has substantially advanced the extraction and analysis of the MOF synthesis literature, with precision, recall, and F1 scores exceeding 90%.
We elucidated two crucial insights from the data set of synthesis conditions. First, the data can be employed to construct predictive models for reaction outcomes, which shed light on the key experimental factors that influence the MOF crystallization process. Second, it is possible to create an MOF chatbot that can provide accurate answers based on text mining, thereby improving access to the synthesis data set and achieving a data-to-dialogue transition. This investigation illustrates the potential for rapid advancement inherent in ChatGPT and other LLMs as a proof of concept.
On a fundamental level, this study provides guidance on interacting with LLMs to serve as AI assistants for chemists, accelerating research with minimal prerequisite coding expertise and thus bridging the gap between chemistry and the realms of computational and data science more effectively. Through interaction and chatting, the code and design of experiments can be modified, democratizing data mining and enhancing the landscape of scientific research. Our work sets a foundation for further exploration and application of LLMs across various scientific domains, paving the way for a new era of AI-assisted chemistry research.
ChatGPT accelerates chemistry discovery for climate response, study shows
By Rachel Leven | August 7, 2023
Yaghi said. “AI has transformed many other sectors of our society – commerce, banking, travel. Why not transform science?”
These datasets on the synergy of the highly-porous materials known as metal-organic frameworks (MOFs) will inform predictive models. The models will accelerate chemists’ ability to create or optimize MOFs, including ones that alleviate water scarcity and capture air pollution. All chemists – not just coders – can build these databases due to the use of AI-fueled chatbots.
To help them teach ChatGPT to generate accurate and relevant information, they modified an approach called “prompt engineering” into “ChemPrompt Engineering.” They developed prompts that avoided asking ChatGPT for made up or misleading content; laid out detailed directions that explained to the chatbot the context and format for the response; and provided the large language model a template or instructions for extracting data.
The chatbot’s literature review – and the experts’ approach – was successful. ChatGPT finished in a fraction of an hour what would have taken a student years to complete, said Borgs, BIDMaP’s director. It mined the synthetic conditions of MOFs with 95% accuracy, Yaghi said.
ChatGPT Searches and Advent of Meta Threads: What it Means for Social Media and Science 3.0
Curator: Stephen J. Williams, PhD
The following explains how popular ChatGPT has become and how the latest social media platforms, including Meta’s (FaceBook) new platform Threads, is becoming as popular or more popular than older social Platforms. In fact, since its short inception since last week (Threads launced 7/07/2023), Threads is threatening Twitter for dominance in that market.
U.S. searches for ChatGPT overtake TikTok, Pinterest, and Zoom
Google searches for ChatGPT have overtaken TikTok in the U.S., jumping to 7.1 million monthly searches compared to 5.1 million
The term ‘ChatGPT’ is now one of the top 100 search terms in the U.S., ranking 92nd, according to Ahrefs data
ChatGPT is now searched more than most major social networks, including LinkedIn, Pinterest, TikTok, and Reddit
Analysis of Google search data reveals that online searches for ChatGPT, the popular AI chatbot, have overtaken most popular social networks in the U.S. This comes when search interest in artificial intelligence is at its highest point in history.
The findings by Digital-adoption.com reveal that US-based searches for ChatGPT have exploded and overtaken popular social networks, such as LinkedIn, Pinterest, and Tiktok, some by millions.
Ranking
Keyword
US Search Volume (Monthly)
1
Facebook
70,920,000
2
YouTube
69,260,000
3
Twitter
15,440,000
4
Instagram
12,240,000
5
ChatGPT
7,130,000
6
LinkedIn
6,990,000
7
Pinterest
5,790,000
8
TikTok
5,130,000
9
Reddit
4,060,000
10
Snapchat
1,280,000
11
WhatsApp
936,000
Since its release in November 2022, searches for ChatGPT have overtaken those of most major social networks. According to the latest June search figures by search tool Ahrefs, searches for ‘ChatGPT’ and ‘Chat GPT’ are made 7,130,000 times monthly in the U.S.
That’s more than the monthly search volume for most of the top ten social networks, including LinkedIn, Pinterest, and TikTok. TikTok is one of the largest growing social media apps, with 100 million users in just a year.
The term ‘ChatGPT’ is now one of the top 100 search terms in the U.S., ranking 92nd, according to Ahrefs data
Searches for ChatGPT have eclipsed other major networks in the U.S., such as Reddit, by millions.
Every day search terms such as ‘maps’ and ‘flights’ have even seen their search volumes pale compared to the rising popularity of ChatGPT. ‘Maps’ is currently searched 440,000 times less than the chatbot each month, and ‘Flights’ is now Googled 2.2 million times less.
2023 has been a breakout year for AI, as searches for the term have more than doubled from 17 million in January 2023 to 42 million in May. In comparison, there were 7.9 million searches in January 2022. There has been an 825% increase in searches for ‘AI’ in the US compared to the average over the last five years.
There is a correlation between the uptick and the public releases of accessible AI chatbots such as ChatGPT, released on November 30, 2022, and Bing AI and Google Bard, released in May 2023.
According to TikTok data, interest in artificial intelligence has soared tenfold since 2020, and virtual reality has more than tripled.
AI has been a big topic of conversation this year as accessible AI chatbots and new technologies were released and sparked rapid adoption, prompting tech leaders like Elon Musk to call for AI regulation.
A spokesperson from Digital-adoption.com commented on the findings: “There has been a massive surge in AI interest this year. Apple’s announcement of Vision Pro has captured audiences at the right time, when new AI technologies, like ChatGPT, have become accessible to almost anyone. The rapid adoption of ChatGPT is surprising, with it becoming one of the fastest-growing tools available”.
All data was gathered from Ahrefs and Google Trends.
If using this story, please include a link tohttps://www.digital-adoption.com/ who conducted this study. A linked credit allows us to keep supplying you with content that you may find useful in the future.
Updated July 10, 2023 9:00 am ET / Original July 10, 2023 7:44 am ET
The launch of Meta Platforms’ Threads looks to have outpaced even the viral success of ChatGPT in terms of signing up users. The next challenge will be keeping them around.
Since its inception on Thursday 7/07/2023, Meta’s new Threads platform has been signing up new users at an alarming rate. On rollout date 5 million signed up, then 30 million by next morning and now as of today (7/1/2023) Threads has over 100 million signups. Compare that to Twitter’s 436 million users, of which are tweeting on average 25% less than a few years ago, and it is easy to see why many social media pundits are calling Threads the new Twitter killer app.
Here are a few notes from the New York Times podcast The Daily
Last week, Meta, the parent company of Facebook and Instagram, released Threads, a social media platform to compete with Twitter. In just 16 hours, Threads was downloaded more than 30 million times.
Mike Isaac, who covers tech companies and Silicon Valley for The Times, explains how Twitter became so vulnerable and discusses the challenges Meta faces to create a less toxic alternative.
Guest: Mike Isaac, a technology correspondent for The New York Times.
Background reading:
Threads is onpace to exceed 100 million users within two months, a feat achieved only by ChatGPT.
Here’s what to know about Threads and how it differs from Twitter.
Here are a few notes from the podcast:
Mike Isaac lamented that Twitter has become user unfriendly for a host of reasons. These include:
The instant reply’guys’ – people who reply but don’t really follow you or your thread
Your followers or following are not pushed to top of thread
The auto bots – the automated Twitter bots
Spam feeds
The changes in service and all these new fees: Twitter push to monetize everything – like airlines
Elon Musk wanted to transform Twitter but his history is always cutting, not just trimming the excess but he is known to just eliminate departments just because he either doesn’t want to pay or CAN’T pay. With Twitter he gutted content moderation.
Twitter ad business is plumetting but Musk wants to make Twitter a subscription business (the Blue check mark)
Twitter only gets a couple of million $ per month from Twitter Blue but Musk has to pay billions to just pay the interest on Twitter loan for Twitter puchase years ago
It is known that Musk is not paying rent on some California offices (some are suggesting he defaulted on leases) and Musk is selling Tesla stock to pay for Twitter expenses (why TSLA stock has been falling … the consensus out there)
Twitter is largest compendium of natural language conversations and Musk wanted to limit bots from scraping Twitter data to do AI and NLP on Twitter threads. This is also a grievance from other companies… that these ‘scrapers’ are not paying enough for Twitter data. However as Mike asks why do the little Twitter user have to pay in either fees or cutbacks from service. (the reason why Elon is limiting viewing per day is to limit these bots from scraping Twitter for data)
Another problem is that Twitter does not have its own servers so pays a lot to Google and AWS for server space. It appears Elon and Twitter are running out of money.
META and THREADS
Zuckerberg has spent billions of infrastructure spending and created a massive advertising ecosystem. This is one of the thoughts behind his push and entry into this space. Zuckerberg actually wanted to but Twitter a decade ago.
Usage and growth: The launch of Threads was Thursday 7-07-23. There were 2 million initial signups and by next morning 30 million overnight. Today Monday 7-10-23 there are 100 million, rivaling Twitter’s 436 million accounts. And as Musk keeps canceling Twitter accounts, angering users over fees or usage restrictions, people are looking for a good platform. Mastedon in too technical and not having the adoption like Meta Threads is having. Mike Isaac hopes Threads will not go the way of Google Hangouts or Plus but Google strategy did not involve social media like Facebook.
Signup and issues: Signup on Threads is easy but you need to go through Instagram. Some people have concerns about having their instagram thread put on their Threads feed but Mike had talked to the people at Meta and they are working to allow users to keep the feeds separate, mainly because Meta understands that the Instgagram and Twitter social cultures are different and users may want to keep Threads more business-like.
Important issues for LPBI: Twitter had decided, by end of May 2023 to end their relationship with WordPress JetPack service, in which WordPress posts could automatically be posted to your Twitter account and feed. Twitter is making users like WordPress pay for this API and WordPress said it would be too expensive as Twitter is not making a flat fee but per usage fee. This is a major hindrance even though the Twitter social share button is still active on posts.
Initial conversations between META and WordPress have indicated META will keep this API service free for WordPress.
So a little background on Meta Threads and signup features from Meta (Facebook) website:
Takeaways
Threads is a new app, built by the Instagram team, for sharing text updates and joining public conversations.
You log in using your Instagram account and posts can be up to 500 characters long and include links, photos, and videos up to 5 minutes in length.
We’re working to soon make Threads compatible with the open, interoperable social networks that we believe can shape the future of the internet.
Mark Zuckerberg just announced the initial version of Threads, an app built by the Instagram team for sharing with text. Whether you’re a creator or a casual poster, Threads offers a new, separate space for real-time updates and public conversations. We are working toward making Threads compatible with the open, interoperable social networks that we believe can shape the future of the internet.
Instagram is where billions of people around the world connect over photos and videos. Our vision with Threads is to take what Instagram does best and expand that to text, creating a positive and creative space to express your ideas. Just like on Instagram, with Threads you can follow and connect with friends and creators who share your interests – including the people you follow on Instagram and beyond. And you can use our existing suite of safety and user controls.
Join the Conversation from Instagram
It’s easy to get started with Threads: simply use your Instagram account to log in. Your Instagram username and verification will carry over, with the option to customize your profile specifically for Threads.
Everyone who is under 16 (or under 18 in certain countries) will be defaulted into a private profile when they join Threads. You can choose to follow the same accounts you do on Instagram, and find more people who care about the same things you do. The core accessibility features available on Instagram today, such as screen reader support and AI-generated image descriptions, are also enabled on Threads.
Your feed on Threads includes threads posted by people you follow, and recommended content from new creators you haven’t discovered yet. Posts can be up to 500 characters long and include links, photos, and videos up to 5 minutes in length. You can easily share a Threads post to your Instagram story, or share your post as a link on any other platform you choose.
Tune Out the Noise
We built Threads with tools to enable positive, productive conversations. You can control who can mention you or reply to you within Threads. Like on Instagram, you can add hidden words to filter out replies to your threads that contain specific words. You can unfollow, block, restrict or report a profile on Threads by tapping the three-dot menu, and any accounts you’ve blocked on Instagram will automatically be blocked on Threads.
As with all our products, we’re taking safety seriously, and we’ll enforce Instagram’s Community Guidelines on content and interactions in the app. Since 2016 we’ve invested more than $16 billion in building up the teams and technologies needed to protect our users, and we remain focused on advancing our industry-leading integrity efforts and investments to protect our community.
Compatible with Interoperable Networks
Soon, we are planning to make Threads compatible with ActivityPub, the open social networking protocol established by the World Wide Web Consortium (W3C), the body responsible for the open standards that power the modern web. This would make Threads interoperable with other apps that also support the ActivityPub protocol, such as Mastodon and WordPress – allowing new types of connections that are simply not possible on most social apps today. Other platforms including Tumblr have shared plans to support the ActivityPub protocol in the future.
We’re committed to giving you more control over your audience on Threads – our plan is to work with ActivityPub to provide you the option to stop using Threads and transfer your content to another service. Our vision is that people using compatible apps will be able to follow and interact with people on Threads without having a Threads account, and vice versa, ushering in a new era of diverse and interconnected networks. If you have a public profile on Threads, this means your posts would be accessible from other apps, allowing you to reach new people with no added effort. If you have a private profile, you’d be able to approve users on Threads who want to follow you and interact with your content, similar to your experience on Instagram.
The benefits of open social networking protocols go well beyond the ways people can follow each other. Developers can build new types of features and user experiences that can easily plug into other open social networks, accelerating the pace of innovation and experimentation. Each compatible app can set its own community standards and content moderation policies, meaning people have the freedom to choose spaces that align with their values. We believe this decentralized approach, similar to the protocols governing email and the web itself, will play an important role in the future of online platforms.
Threads is Meta’s first app envisioned to be compatible with an open social networking protocol – we hope that by joining this fast-growing ecosystem of interoperable services, Threads will help people find their community, no matter what app they use.
What’s Next
We’re rolling out Threads today in more than 100 countries for iOS and Android, and people in those countries can download the app from the Apple App Store and Google Play Store.
In addition to working toward making Threads compatible with the ActivityPub protocol, soon we’ll be adding a number of new features to help you continue to discover threads and creators you’re interested in, including improved recommendations in feed and a more robust search function that makes it easier to follow topics and trends in real time.
Should Science Migrate over to Threads Instead of Twitter?
I have written multiple time of the impact of social media, Science and Web 2.0 and the new Science and Web 3.0 including
It, as of this writing, appears it is not crucial that scientific institutions need to migrate over to Threads yet, although the impetus is certainly there. Many of the signups have of course been through Instagram (which is the only way to signup for now) and a search of @Threads does not show that large scientific organizations have signed up for now.
A search for NIH, NCBI, AACR, and Personalized Medicine Coalition or PMC which is the big MGH orgaization on personalized medicine appears to return nothing yet. Pfizer and most big pharma is on @Threads now but that is because they maintain a marketing thread on Instagram. How necessary is @Threads for communicating science over Science 3.0 platform remains to be seen. In addition, how will @Threads be used for real time scientific conference coverage? Will Meta be able to integrate with virtual reality?
Other articles of Note on this Open Access Scientific Journal Include:
OpenAI and ChatGPT face unique legal challenges over CopyRight Laws
Reporter: Stephen J. Williams, PhD
In previous weeks on this page and on the sister page ChatGPT applied to Cancer & Oncology, a comparison between ChatGPT, OpenAI, and Google large language model based search reveals a major difference between the algorithms with repect to citation and author credit. In essence while Google returns a hyperlink to the information used to form an answer, ChatGPT and OpenAI are agnostic in crediting or citing the sources of information used to generate answers to queries. With ChatGPT the source data, or more specifically the training set used for the AI algorithm is never properly cited in the query results.
This, as outlined below, is making a big problem when it comes to copyright law and intelectual property. Last week a major lawsuit has been filed because of incorrect and citing, referencing, and attribution of ownership of intellectual property.
As Miles Klee reports in The Rolling Stone
“OpenAI faces allegations of privacy invasion and violating authors’ copyright — but this may be just the tip of the iceberg”
The burgeoning AI industry has just crossed another major milestone, with two new class-action lawsuits calling into question whether this technology violates privacy rights, scrapes intellectual property without consent and negatively affects the public at large. Experts believe they’re likely to be the first in a wave of legal challenges to companies working on such products. Both suits were filed on Wednesday and target OpenAI, a research lab consisting of both a nonprofit arm and a corporation, over ChatGPT software, a “large language model” capable of generating human-like responses to text input. One, filed by Clarkson, a public interest law firm, is wide-ranging and invokes the potentially “existential” threat of AI itself. The other, filed by the Joseph Saveri Law Firm and attorney Matthew Butterick, is focused on two established authors, Paul Tremblay and Mona Awad, who claim that their books were among those ChatGPT was trained on — a violation of copyright, according to the complaint. (Saveri and Butterick are separately pursuing legal action against OpenAI, GitHub and Microsoft over GitHub Copilot, an AI-based coding product that they argue “appears to profit from the work of open-source programmers by violating the conditions of their open-source licenses.”)
Saveri and Butterick’s latest suit goes after OpenAI for direct copyright infringement as well as violations of the Digital Millennium Copyright Act (DMCA). Tremblay (who wrote the novel The Cabin at the End of the World) and Awad (author of 13 Ways of Looking at a Fat Girl and Bunny) are the representatives of a proposed class of plaintiffs who would seek damages as well as injunctive relief in the form of changes to ChatGPT. The filing includes ChatGPT’s detailed responses to user questions about the plots of Tremblay’s and Awad’s books — evidence, the attorneys argue, that OpenAI is unduly profiting off of infringed materials, which were scraped by the chat bot. While the suits venture into uncharted legal territory, they were more or less inevitable, according to those who research AI tech and privacy or practice law around those issues.
“[AI companies] should have and likely did expect these types of challenges,” says Ben Winters, senior counsel at the Electronic Privacy Information Center and head of the organization’s AI and Human Rights Project. He points out that OpenAI CEO Sam Altman mentioned a few prior “frivolous” suits against the company during his congressional testimony on artificial intelligence in May. “Whenever you create a tool that implicates so much personal data and can be used so widely for such harmful and otherwise personal purposes, I would be shocked there is not anticipated legal fire,” Winters says. “Particularly since they allow this sort of unfettered access for third parties to integrate their systems, they end up getting more personal information and more live information that is less publicly available, like keystrokes and browser activity, in ways the consumer could not at all anticipate.”
They say that OpenAI defendants “profit richly” from the use of their copyrighted materials and yet the authors never consented to the use of their copyrighted materials without credit or compensation.
ChatGPT lawsuit says OpenAI has previously utilized illegal ‘shadow libraries’ for AI training datasets
Although many types of material are used to train large language models, “books offer the best examples of high-quality longform writing,” according to the ChatGPT lawsuit.
OpenAI has previously utilized books for its AI training datasets, including unpublished novels (the majority of which were under copyright) available on a website that provides the materials for free. The plaintiffs suggest that OpenAI may have utilized copyrighted materials from “flagrantly illegal shadow libraries.”
Tremblay and Awad note that OpenAI’s March 2023 paper introducing GPT-4 failed to include any information about the training dataset. However, they say that ChatGPT was able to generate highly accurate summaries of their books when prompted, suggesting that their copyrighted material was used in the training dataset without their consent.
They filed the ChatGPT class action lawsuit on behalf of themselves and a proposed class of U.S. residents and entities that own a U.S. copyright for any work used as training data for the OpenAI language models during the class period.
Earlier this year, a tech policy group urged federal regulators to block OpenAI’s GPT-4 AI product because it does not meet federal standards.
What is the general consensus among legal experts on generative AI and copyright?
Given the hype around ChatGPT and the speculation that it could be widely used, it is important to understand the legal implications of the technology. First, do copyright owners of the text used to train ChatGPT have a copyright infringement claim against OpenAI? Second, can the output of ChatGPT be protected by copyright and, if so, who owns that copyright?
To answer these questions, we need to understand the application of US copyright law.
Copyright Law Basics
Based on rights in Article I, Section 8 of the Constitution, Congress passed the first copyright law in 1790. It has been amended several times. Today, US copyright law is governed by the Copyright Act of 1976. This law grants authors of original works exclusive rights to reproduce, distribute, and display their work. Copyright protection applies from the moment of creation, and, for most works, the copyright term is the life of the author plus 70 years after the author’s death. Under copyright law, the copyright holder has the exclusive right to make copies of the work, distribute it, display it publicly, and create derivative works based on it. Others who want to use the work must obtain permission from the copyright holder or use one of the exceptions to copyright law, such as fair use.
The purpose of copyright law is to incentivize authors to create novel and creative works. It does this by granting authors exclusive rights to control the use of their work, thus allowing them to financially benefit from their works. Copyright law also encourages the dissemination of knowledge by allowing others to use copyrighted works under certain conditions, such as through the fair use doctrine, which allows for limited use of copyrighted material for the purposes of criticism, commentary, news reporting, teaching, scholarship, or research. By protecting the rights of authors and creators while also allowing for the use of copyrighted works for the public benefit, copyright law aims to strike a balance between the interests of authors and the public.
Inputs – Training ChatGPT with Copyrighted Material
ChatGPT was trained on a large training dataset sourced from the internet, including a vast amount of text from websites, articles, books, social media posts, and academic papers. Importantly, ChatGPT was not aware of the source of the data, it only saw the text and learned the patterns and relationships between the words, phrases and sentences. The vast majority of the text used to train ChatGPT was certainly subject to copyright protection—except for text that is in the public domain like facts or discoveries or works whose term of copyright protection has ended.
Did the ChatGPT training process violate the copyright of the original authors? To answer that question we must determine: if during the training process OpenAI copied the underlying works—because copyright infringement requires an act of copying works that are protected by copyright; is the output of ChatGPT a “derivative work” under copyright law; and would such copying or production of a derivate work fall under the “fair use” exception of copyright law.
Copying During Training
We are not aware of publicly available information regarding whether, during the training process, the training text for ChatGPT was copied or simply referenced. Therefore, we asked ChatGPT and received this answer:
Prompt: During the ChatGPT training process, was the underlying training text copied into a OpenAI database?
Answer: During the training process, text from various sources is used to train the ChatGPT model. It is likely that the text was copied into an internal database at OpenAI for the purpose of training the model. However, the training text is typically preprocessed to remove any sensitive information such as personal identifiers, copyrighted text, etc. In addition, the text is also used to train the model and not stored in a database. The model uses the text to learn patterns and structure of the language and once the training is done, it doesn’t require the text anymore.
So, it seems that during the training process, text was copied. It is also interesting that ChatGPT stated that the training text was “preprocessed” to remove any copyrighted text. That seems highly unlikely since otherwise nearly all text would have been removed.
Is ChatGPT Output a Derivative Work?
Under US copyright law, the owner of a copyright has the exclusive right “to prepare derivative works based upon the copyrighted work.” A “derivative work” is “a work based upon one or more preexisting works.” ChatGPT is trained on preexisting works and generates output based on that training.
As Daniel Gervais, a professor at Vanderbilt Law School who specializes in intellectual property law, says, the definition of a derivative work under copyright law “could loosely be used as a definition of machine learning when applied to the creation of literary and artistic productions because AI machines can produce literary and artistic content (output) that is almost necessarily ‘based upon’ a dataset consisting of preexisting works.” Under this view, it seems that all ChatGPT output is a derivative work under copyright law.
On a related point, it is worth noting that in producing its output, ChatGPT is not “copying” anything. ChatGPT generates text based on the context of the input and the words and phrase patterns it was trained on. ChatGPT is not “copying” and then changing text.
What About Fair Use?
Let’s assume that the underlying text was copied in some way during the ChatGPT training process. Let’s further assume that outputs from Chatto are, at least sometimes, derivative works under copyright law. If that is the case, do copyright owners of the original works have a copyright infringement claim against OpenAI? Not if the copying and the output generation are covered by the doctrine of “fair use.” If a use qualifies as fair use, then actions that would otherwise be prohibited would not be deemed an infringement of copyright.
In determining whether the use made of a work in any particular case is a fair use, the factors include:
The purpose and character of the use, including whether such use is of a commercial nature or is for nonprofit educational purposes.
The nature of the copyrighted work.
The amount and substantiality of the portion used in relation to the copyrighted work as a whole.
The effect of the use upon the potential market for or value of the copyrighted work.
In this case, assuming OpenAI copied copyrighted text as part of the ChatGPT training process, such copying was not for a commercial purpose and had no economic impact on the copyright owner. Daniel Gervais says “it is much more likely than not” that training systems on copyrighted data will be covered by fair use.
In determining if a commercial use will be considered “fair use,” the courts will primarily look at the scope and purpose of the use and the economic impact of such use. Does the use in question change the nature of the underlying copyright material in some material way (described as a “transformative” use) and does it economically impact the original copyright holder?
Without a specific example, it is difficult to determine exactly if a resulting output from ChatGPT would be fair use. The fact that ChatGPT does not copy and has been trained on millions of underlying works, it seems likely most output would be fair use—without using significant portions of any one protected work. In addition, because of the vast corpus of text used to train ChatGPT, it seems unlikely that ChatGPT output will have a negative economic impact on any one copyright holder. But, given the capabilities of ChatGPT, that might not always be the case.
Imagine if you asked ChatGPT to “Write a long-form, coming of age, story in the style of J.K. Rowling, using the characters from Harry Potter and the Chamber of Secrets.” In that case, it would seem that the argument for fair use would be weak. This story could be sold to the public and could conceivably have a negative economic impact on J.K. Rowling. A person that wants to read a story about Harry Potter might buy this story instead of buying a book by J. K. Rowling.
Finally, it is worth noting that OpenAI is a non-profit entity that is a “AI research and deployment company.” It seems that OpenAI is the type of research company, and ChatGPT is the type of research project, that would have a strong argument for fair use. This practice has been criticized as “AI Data Laundering,” shielding commercial entities from liability by using a non-profit research institution to create the data set and train AI engines that might later be used in commercial applications.
Outputs – Can the Output of ChatGPT be Protected by Copyright
Is the output of ChatGPT protected by copyright law and, if so, who is the owner? As an initial matter, does the ChatGPT textual output fit within the definition of what is covered under copyright law: “original works of authorship fixed in any tangible medium of expression.”
The text generated by ChatGPT is the type of subject matter that, if created by a human, would be covered by copyright. However, most scholars have opined, and the US Copyright Office has ruled that the output of generative AI systems, like ChatGPT, are not protectable under US copyright law because the work must be an original, creative work of a human author.
In 2022, the US Copyright Office, ruling on whether a picture generated completely autonomously by AI could be registered as a valid copyright, stated “[b]because copyright law as codified in the 1976 Act requires human authorship, the [AI Generated] Work cannot be registered.” The U.S. Copyright Office has issued several similar statements, informing creators that it will not register copyright for works produced by a machine or computer program. The human authorship requirement of the US Copyright Office is set forth as follows:
The Human Authorship Requirement – The U.S. Copyright Office will register an original work of authorship, provided that the work was created by a human being. The copyright law only protects “the fruits of intellectual labor” that “are founded in the creative powers of the mind.” Trade-Mark Cases, 100 U.S. 82, 94 (1879).
While such policies are not binding on the courts, the stance by the US Copyright Office seems to be in line with the purpose of copyright law flowing from the Constitution: to incentivize humans to produce creative works by giving them a monopoly over their creations for a limited period of time. Machines, of course, need and have no such motivation. In fact, copyright law expressly allows a corporation or other legal entity to be the owner of a copyright under the “work made for hire” doctrine. However, to qualify as a work made for hire, the work must be either work prepared by an employee within the scope of his or her employment, or be prepared by a party who “expressly agrees in a written instrument signed by them that the work shall be considered a work made for hire.” Only humans can be employees and only humans or corporations can enter a legally binding contract—machines cannot.
Other articles of note in this Open Access Scientific Journal on ChatGPT and Open AI Include:
The Use of ChatGPT in the World of BioInformatics and Cancer Research and Development of BioGPT by MIT
Curator: Stephen J. Williams, Ph.D.
Chatbots are being used in multiple interdisciplanary areas in research and medicine and so it was a natural progression to incorporate artificial intelligence (AI), natural language processing (NLP), and chatbot technology like ChatGPT into bioinformatic analysis.
“In domains like informatics, management and marketing, media and communication science, languages and philosophy, psychology and sociology, engineering, design, and human-computer interaction, the fast expanding body of chatbot study is clearly interdisciplinary.
The field of bioinformatics is a natural fit for incorporting this technology. The curated information below shows some use examples of this technology in bioinformatics related to cancer research.
How ChatGPT can be used in bioinformatics research?
ChatGPT is a variant of the GPT (Generative Pre-trained Transformer) language model that was designed to generate human-like text in a conversational setting. It is not directly related to bioinformatics, which is the field of study that deals with the storage, retrieval, and analysis of biological data, particularly in the context of genetics and genomics. However, ChatGPT could potentially be used in a bioinformatics context as a tool for generating natural language descriptions of genetic or genomic data, or for generating responses to queries about such data.
For example, a researcher could use ChatGPT to generate descriptions of genetic variants or gene expression patterns based on input data. This could be useful for generating summaries of results for reports or papers, or for generating explanations of complex concepts for non-expert audiences. ChatGPT could also be used to generate responses to queries about genetic or genomic data, such as “What is the function of gene X?” or “What are the potential consequences of variant Y?”
It’s worth noting that ChatGPT is just one of many tools and techniques that can be used in bioinformatics, and it is unlikely to be the most suitable or effective option in every situation. There are many specialized tools and resources available for working with biological data, and it is often necessary to use a combination of these tools to fully analyze and understand the data.
Generating descriptions of genetic or genomic data: ChatGPT could be used to generate natural language descriptions of genetic or genomic data based on input data. For example, suppose a researcher has a dataset containing information about gene expression levels in different tissues. The researcher could use ChatGPT to generate a description of the data, such as:
“Gene X is highly expressed in the liver and kidney, with moderate expression in the brain and heart. Gene Y, on the other hand, shows low expression in all tissues except for the lung, where it is highly expressed.”
Thereby ChatGPT, at its simplest level, could be used to ask general questions like “What is the function of gene product X?” and a ChatGPT could give a reasonable response without the scientist having to browse through even highly curated databases lie GeneCards or UniProt or GenBank. Or even “What are potential interactors of Gene X, validated by yeast two hybrid?” without even going to the curated InterActome databases or using expensive software like Genie.
Summarizing results: ChatGPT could be used to generate summaries of results from genetic or genomic studies. For example, a researcher might use ChatGPT to generate a summary of a study that found a association between a particular genetic variant and a particular disease. The summary might look something like this:
“Our study found that individuals with the variant form of gene X are more likely to develop disease Y. Further analysis revealed that this variant is associated with changes in gene expression that may contribute to the development of the disease.”
It’s worth noting that ChatGPT is just one tool that could potentially be used in these types of applications, and it is likely to be most effective when used in combination with other bioinformatics tools and resources. For example, a researcher might use ChatGPT to generate a summary of results, but would also need to use other tools to analyze the data and confirm the findings.
ChatGPT is a variant of the GPT (Generative Pre-training Transformer) language model that is designed for open-domain conversation. It is not specifically designed for generating descriptions of genetic variants or gene expression patterns, but it can potentially be used for this purpose if you provide it with a sufficient amount of relevant training data and fine-tune it appropriately.
To use ChatGPT to generate descriptions of genetic variants or gene expression patterns, you would first need to obtain a large dataset of examples of descriptions of genetic variants or gene expression patterns. You could use this dataset to fine-tune the ChatGPT model on the task of generating descriptions of genetic variants or gene expression patterns.
Here’s an example of how you might use ChatGPT to generate a description of a genetic variant:
First, you would need to pre-process your dataset of descriptions of genetic variants to prepare it for use with ChatGPT. This might involve splitting the descriptions into individual sentences or phrases, and encoding them using a suitable natural language processing (NLP) library or tool.
Next, you would need to fine-tune the ChatGPT model on the task of generating descriptions of genetic variants. This could involve using a tool like Hugging Face’s Transformers library to load the ChatGPT model and your pre-processed dataset, and then training the model on the task of generating descriptions of genetic variants using an appropriate optimization algorithm.
Once the model has been fine-tuned, you can use it to generate descriptions of genetic variants by providing it with a prompt or seed text and asking it to generate a response. For example, you might provide the model with the prompt “Generate a description of a genetic variant associated with increased risk of breast cancer,” and ask it to generate a response. The model should then generate a description of a genetic variant that is associated with increased risk of breast cancer.
It’s worth noting that generating high-quality descriptions of genetic variants or gene expression patterns is a challenging task, and it may be difficult to achieve good results using a language model like ChatGPT without a large amount of relevant training data and careful fine-tuning.
To train a language model like chatGPT to extract information about specific genes or diseases from research papers, you would need to follow these steps:
Gather a large dataset of research papers that contain information about the specific genes or diseases you are interested in. This dataset should be diverse and representative of the types of papers you want the model to be able to extract information from.
Preprocess the text data in the research papers by tokenizing the text and creating a vocabulary. You may also want to consider lemmatizing or stemming the text to reduce the dimensionality of the dataset.
Train the language model on the preprocessed text data. You may want to fine-tune a pre-trained model such as chatGPT on your specific dataset, or you can train a new model from scratch.
ChatGPT could also be useful for sequence analysis
A few examples of sequence analysis a ChatGPT could be useful include:
Protein structure
Identifying functional regions of a protein
Predicting protein-protein interactions
Identifying protein homologs
Generating Protein alignments
All this could be done without having access to UNIX servers or proprietary software or knowing GCG coding
ChatGPT in biomedical research
There are several potential ways that ChatGPT or other natural language processing (NLP) models could be applied in biomedical research:
Text summarization: ChatGPT or other NLP models could be used to summarize large amounts of text, such as research papers or clinical notes, in order to extract key information and insights more quickly.
Data extraction: ChatGPT or other NLP models could be used to extract structured data from unstructured text sources, such as research papers or clinical notes. For example, the model could be trained to extract information about specific genes or diseases from research papers, and then used to create a database of this information for further analysis.
Literature review: ChatGPT or other NLP models could be used to assist with literature review tasks, such as identifying relevant papers, extracting key information from papers, or summarizing the main findings of a group of papers.
Predictive modeling: ChatGPT or other NLP models could be used to build predictive models based on large amounts of text data, such as electronic health records or research papers. For example, the model could be trained to predict the likelihood of a patient developing a particular disease based on their medical history and other factors.
It’s worth noting that while NLP models like ChatGPT have the potential to be useful tools in biomedical research, they are only as good as the data they are trained on, and it is important to carefully evaluate the quality and reliability of any results generated by these models.
ChatGPT in text mining of biomedical data
ChatGPT could potentially be used for text mining in the biomedical field in a number of ways. Here are a few examples:
Extracting information from scientific papers: ChatGPT could be trained on a large dataset of scientific papers in the biomedical field, and then used to extract specific pieces of information from these papers, such as the names of compounds, their structures, and their potential uses.
Generating summaries of scientific papers: ChatGPT could be used to generate concise summaries of scientific papers in the biomedical field, highlighting the main findings and implications of the research.
Identifying trends and patterns in scientific literature: ChatGPT could be used to analyze large datasets of scientific papers in the biomedical field and identify trends and patterns in the data, such as emerging areas of research or common themes among different papers.
Generating questions for further research: ChatGPT could be used to suggest questions for further research in the biomedical field based on existing scientific literature, by identifying gaps in current knowledge or areas where further investigation is needed.
Generating hypotheses for scientific experiments: ChatGPT could be used to generate hypotheses for scientific experiments in the biomedical field based on existing scientific literature and data, by identifying potential relationships or associations that could be tested in future research.
PLEASE WATCH VIDEO
In this video, a bioinformatician describes the ways he uses ChatGPT to increase his productivity in writing bioinformatic code and conducting bioinformatic analyses.
He describes a series of uses of ChatGPT in his day to day work as a bioinformatian:
Using ChatGPT as a search engine: He finds more useful and relevant search results than a standard Google or Yahoo search. This saves time as one does not have to pour through multiple pages to find information. However, a caveat is ChatGPT does NOT return sources, as highlighted in previous postings on this page. This feature of ChatGPT is probably why Microsoft bought OpenAI in order to incorporate ChatGPT in their Bing search engine, as well as Office Suite programs
ChatGPT to help with coding projects: Bioinformaticians will spend multiple hours searching for and altering open access available code in order to run certain function like determining the G/C content of DNA (although there are many UNIX based code that has already been established for these purposes). One can use ChatGPT to find such a code and then assist in debugging that code for any flaws
ChatGPT to document and add coding comments: When writing code it is useful to add comments periodically to assist other users to determine how the code works and also how the program flow works as well, including returned variables.
One of the comments was interesting and directed one to use BIOGPT instead of ChatGPT
0:54 oh dear. You cannot use chatgpt like that in Bioinformatics as it is rn without double checking the info from it. You should be using biogpt instead for paper summarisation. ChatGPT goes for human-like responses over precise information recal. It is quite good for debugging though and automating boring awkward scripts
The BioGPT model was proposed in BioGPT: generative pre-trained transformer for biomedical text generation and mining by Renqian Luo, Liai Sun, Yingce Xia, Tao Qin, Sheng Zhang, Hoifung Poon and Tie-Yan Liu. BioGPT is a domain-specific generative pre-trained Transformer language model for biomedical text generation and mining. BioGPT follows the Transformer language model backbone, and is pre-trained on 15M PubMed abstracts from scratch.
The abstract from the paper is the following:
Pre-trained language models have attracted increasing attention in the biomedical domain, inspired by their great success in the general natural language domain. Among the two main branches of pre-trained language models in the general language domain, i.e. BERT (and its variants) and GPT (and its variants), the first one has been extensively studied in the biomedical domain, such as BioBERT and PubMedBERT. While they have achieved great success on a variety of discriminative downstream biomedical tasks, the lack of generation ability constrains their application scope. In this paper, we propose BioGPT, a domain-specific generative Transformer language model pre-trained on large-scale biomedical literature. We evaluate BioGPT on six biomedical natural language processing tasks and demonstrate that our model outperforms previous models on most tasks. Especially, we get 44.98%, 38.42% and 40.76% F1 score on BC5CDR, KD-DTI and DDI end-to-end relation extraction tasks, respectively, and 78.2% accuracy on PubMedQA, creating a new record. Our case study on text generation further demonstrates the advantage of BioGPT on biomedical literature to generate fluent descriptions for biomedical terms.
Tips:
BioGPT is a model with absolute position embeddings so it’s usually advised to pad the inputs on the right rather than the left.
BioGPT was trained with a causal language modeling (CLM) objective and is therefore powerful at predicting the next token in a sequence. Leveraging this feature allows BioGPT to generate syntactically coherent text as it can be observed in the run_generation.py example script.
The model can take the past_key_values (for PyTorch) as input, which is the previously computed key/value attention pairs. Using this (past_key_values or past) value prevents the model from re-computing pre-computed values in the context of text generation. For PyTorch, see past_key_values argument of the BioGptForCausalLM.forward() method for more information on its usage.
This model was contributed by kamalkraj. The original code can be found here.
BioGPT is MIT-licensed. The license applies to the pre-trained models as well.
Contributing
This project welcomes contributions and suggestions. Most contributions require you to agree to a Contributor License Agreement (CLA) declaring that you have the right to, and actually do, grant us the rights to use your contribution. For details, visit https://cla.opensource.microsoft.com.
When you submit a pull request, a CLA bot will automatically determine whether you need to provide a CLA and decorate the PR appropriately (e.g., status check, comment). Simply follow the instructions provided by the bot. You will only need to do this once across all repos using our CLA.
As of right now this does not seem Open Access, however a sign up is required!
We provide our pre-trained BioGPT model checkpoints along with fine-tuned checkpoints for downstream tasks, available both through URL download as well as through the Hugging Face 🤗 Hub.
Luo R, Sun L, Xia Y, Qin T, Zhang S, Poon H, Liu TY.Brief Bioinform. 2022 Nov 19;23(6):bbac409. doi: 10.1093/bib/bbac409.PMID: 36156661
We evaluate BioGPT on six biomedical natural language processing tasks and demonstrate that our model outperforms previous models on most tasks. …Our case study on text generation further demonstrates the advantage of BioGPT on biomedical literature to generate fl …
Here they show the advantages of BioGPT over BioBERT and ChatGPT in an example of text extraction and question answer
Table 7. Example of generated text
Input Model Text
Bicalutamide GPT-2 Bicalutamide, a synthetic bicalutamide derivative, was found to increase the cellular proliferation
of C. elegans cells. This effect was not observed with the other synthetic bicalutamide derivatives. This is in line with our previous work which showed that bicalutamide increases the proliferation of C. elegans cells but not in the presence of synthetic bicalutamide.
BioGPT Bicalutamide (Casodex) is an androgen receptor (AR) antagonist approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in patients who have progressed on or are ineligible for docetaxel chemotherapy, as well as for the treatment of early-stage prostate cancer in men who have not progressed on or are ineligible for docetaxel chemotherapy, as well as for the treatment of metastatic castration-sensitive prostate cancer (mCSPC) in men who have not progressed on or are ineligible for docetaxel chemotherapy.
Janus kinase 3 (JAK-3) GPT-2 Janus kinase 3 (JAK-3) mediates the conversion of glucose to glycogen in skeletal muscle. The
increase in glucose uptake by skeletal muscle is believed to be associated with a reduction in muscle protein breakdown and with the release of ketone bodies, which contribute to the metabolism of glucose.
BioGPT Janus kinase 3 (JAK-3) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and plays an important role in the regulation of cell proliferation, differentiation, survival, migration and angiogenesis.
Apricitabine GPT-2 Apricitabine, duloxetine and citalopram) were investigated in patients with a history of
treatment-resistant depression (n = 10). We found that treatment with the three drugs significantly decreased depressive symptoms, but not depressive symptoms over the next 12 weeks. We conclude that antidepressant drugs that reduce depressive symptoms and reduce depressive symptoms over time may be beneficial in patients with recurrent depression.
BioGPT Apricitabine is an oral prodrug of 5-aza-2 ’-deoxycytidine (5-aza-CdR), a DNA methyltransferase (DNMT) inhibitor, which has been approved by the US Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in combination with low-dose cytarabine (Ara-C) and granulocyte colony-stimulating factor (G-CSF) for patients with intermediate-2 or high-risk MDS or AML.
Xylazine GPT-2 Xylazine, the ‘active ingredient’ in ‘bath salts’ (see above) has been linked to numerous deaths,
including those of former University of California, Berkeley, professor Andrew Anglin, who posted
a video of himself having a bath filled with it.
BioGPT Xylazine is an alpha 2-adrenoceptor agonist which has been used as a sedative and analgesic in veterinary medicine for many years, but its effects on the cardiovascular system have not been extensively studied in the dog, and its effects on the central nervous system (CNS) have not been well characterized in the dog, despite the fact that xylazine has been widely used as a sedative and analgesic in veterinary medicine for more than 30 years.
Psoralen GPT-2 Psoralen, the city of the spiritualist, and had been given to him by God, who wished to show him
the way of salvation, and to draw him back to the true life of Christ, and to bring him into communion with his fellow-man.
BioGPT Psoralen photochemotherapy (PUVA) is a well-established treatment for psoriasis, but its use is limited by the risk of skin cancer, particularly squamous cell carcinoma (SCC) of the head and neck (H & N), which is the most common site of skin cancer in the United States (US)
CP-673451 GPT-2 CP-673451) and 4-5-6-3-1-2-3-4-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20-21-22-23-24-25-26-27-
BioGPT CP-673451 is a potent, selective, and orally active inhibitor of human neutrophil elastase (HNE) and human cathepsin G (CatG) with in vitro and in vivo anti-inflammatory activity in a variety of animal models of inflammation and in a model of acute lung injury (ALI) in the rat induced by intratracheal instillation of lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha), a model of acute lung injury (ALI) in which neutrophils play an important role.
BIIB-021 GPT-2 BIIB-021A-2-1.pdf. Wright, C. (2002). ‘The War on Terror: A Legal Theory of Terrorist Attacks,’ in
L.E.R. Wright, S.R. Warrick and J.H. Rothman (Eds.), The War on Terror: Essays in Honor of Michael T. Klare (New York: Oxford University Press), 143-57.
BioGPT BIIB-021 is a novel, orally active, non-peptide bradykinin B2 receptor antagonist with potent and long-lasting anti-inflammatory activity in animal models of acute and chronic inflammation and in a rat model of adjuvant-induced arthritis (AIA), an animal model of rheumatoid arthritis (RA) and in a rat model of collagen-induced arthritis (CIA), an animal model of collagen-induced arthritis (CIA), in which arthritis is induced by immunization with bovine type II collagen (CII).
Huang L, Lin J, Li X, Song L, Zheng Z, Wong KC.Brief Bioinform. 2022 Jan 17;23(1):bbab451. doi: 10.1093/bib/bbab451.PMID: 34791012
The rapid growth in literature accumulates diverse and yet comprehensive biomedical knowledge hidden to be mined such as drug interactions. However, it is difficult to extract the heterogeneous knowledge to retrieve or even discover the latest and novel knowledge in an efficient manner. To address such a problem, we propose EGFI for extracting and consolidating drug interactions from large-scale medical literature text data. Specifically, EGFI consists of two parts: classification and generation. In the classification part, EGFI encompasses the language model BioBERT which has been comprehensively pretrained on biomedical corpus. In particular, we propose the multihead self-attention mechanism and packed BiGRU to fuse multiple semantic information for rigorous context modeling. In the generation part, EGFI utilizes another pretrained language model BioGPT-2 where the generation sentences are selected based on filtering rules.
Results: We evaluated the classification part on ‘DDIs 2013’ dataset and ‘DTIs’ dataset, achieving the F1 scores of 0.842 and 0.720 respectively. Moreover, we applied the classification part to distinguish high-quality generated sentences and verified with the existing growth truth to confirm the filtered sentences. The generated sentences that are not recorded in DrugBank and DDIs 2013 dataset demonstrated the potential of EGFI to identify novel drug relationships.
Jin Q, Yang Y, Chen Q, Lu Z.ArXiv. 2023 May 16:arXiv:2304.09667v3. Preprint.PMID: 37131884 Free PMC article.
While large language models (LLMs) have been successfully applied to various tasks, they still face challenges with hallucinations. Augmenting LLMs with domain-specific tools such as database utilities can facilitate easier and more precise access to specialized knowledge. In this paper, we present GeneGPT, a novel method for teaching LLMs to use the Web APIs of the National Center for Biotechnology Information (NCBI) for answering genomics questions. Specifically, we prompt Codex to solve the GeneTuring tests with NCBI Web APIs by in-context learning and an augmented decoding algorithm that can detect and execute API calls. Experimental results show that GeneGPT achieves state-of-the-art performance on eight tasks in the GeneTuring benchmark with an average score of 0.83, largely surpassing retrieval-augmented LLMs such as the new Bing (0.44), biomedical LLMs such as BioMedLM (0.08) and BioGPT (0.04), as well as GPT-3 (0.16) and ChatGPT (0.12). Our further analyses suggest that: (1) API demonstrations have good cross-task generalizability and are more useful than documentations for in-context learning; (2) GeneGPT can generalize to longer chains of API calls and answer multi-hop questions in GeneHop, a novel dataset introduced in this work; (3) Different types of errors are enriched in different tasks, providing valuable insights for future improvements.
PLEASE WATCH THE FOLLOWING VIDEOS ON BIOGPT
This one entitled
Microsoft’s BioGPT Shows Promise as the Best Biomedical NLP
gives a good general description of this new MIT/Microsoft project and its usefullness in scanning 15 million articles on PubMed while returning ChatGPT like answers.
Please note one of the comments which is VERY IMPORTANT
bioGPT is difficult for non-developers to use, and Microsoft researchers seem to default that all users are proficient in Python and ML.
Much like Microsoft Azure it seems this BioGPT is meant for developers who have advanced programming skill. Seems odd then to be paying programmers multiK salaries when one or two Key Opinion Leaders from the medical field might suffice but I would be sure Microsoft will figure this out.
ALSO VIEW VIDEO
This is a talk from Microsoft on BioGPT
Other Relevant Articles on Natural Language Processing in BioInformatics, Healthcare and ChatGPT for Medicine on this Open Access Scientific Journal Include
Use of Systems Biology for Design of inhibitor of Galectins as Cancer Therapeutic – Strategy and Software
Curator:Stephen J. Williams, Ph.D.
Below is a slide representation of the overall mission 4 to produce a PROTAC to inhibit Galectins 1, 3, and 9.
Using A Priori Knowledge of Galectin Receptor Interaction to Create a BioModel of Galectin 3 Binding
Now after collecting literature from PubMed on “galectin-3” AND “binding” to determine literature containing kinetic data we generate a WordCloud on the articles.
This following file contains the articles needed for BioModels generation.
From the WordCloud we can see that these corpus of articles describe galectin binding to the CRD (carbohydrate recognition domain). Interestingly there are many articles which describe van Der Waals interactions as well as electrostatic interactions. Certain carbohydrate modifictions like Lac NAc and Gal 1,4 may be important. Many articles describe the bonding as well as surface interactions. Many studies have been performed with galectin inhibitors like TDGs (thio-digalactosides) like TAZ TDG (3-deoxy-3-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside). This led to an interesting article
.
Dual thio-digalactoside-binding modes of human galectins as the structural basis for the design of potent and selective inhibitors
Human galectins are promising targets for cancer immunotherapeutic and fibrotic disease-related drugs. We report herein the binding interactions of three thio-digalactosides (TDGs) including TDG itself, TD139 (3,3′-deoxy-3,3′-bis-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside, recently approved for the treatment of idiopathic pulmonary fibrosis), and TAZTDG (3-deoxy-3-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside) with human galectins-1, -3 and -7 as assessed by X-ray crystallography, isothermal titration calorimetry and NMR spectroscopy. Five binding subsites (A-E) make up the carbohydrate-recognition domains of these galectins. We identified novel interactions between an arginine within subsite E of the galectins and an arene group in the ligands. In addition to the interactions contributed by the galactosyl sugar residues bound at subsites C and D, the fluorophenyl group of TAZTDG preferentially bound to subsite B in galectin-3, whereas the same group favored binding at subsite E in galectins-1 and -7. The characterised dual binding modes demonstrate how binding potency, reported as decreased Kd values of the TDG inhibitors from μM to nM, is improved and also offer insights to development of selective inhibitors for individual galectins.
Figures
Figure 1. Chemical structures of L3, TDG…
Figure 2. Structural comparison of the carbohydrate…
Explanation on “Results of Medical Text Analysis with Natural Language Processing (NLP) presented in LPBI Group’s NEW GENRE Edition: NLP” on Genomics content, standalone volume in Series B and NLP on Cancer content as Part B New Genre Volume 1 in Series C
NEW GENRE Edition, Editor-in-Chief: Aviva Lev-Ari, PhD, RN
Series B: Frontiers in Genomics Research NEW GENRE Audio English-Spanish
PART A: The eTOCs in Spanish in Audio format AND the eTOCs in Bi-lingual format: Spanish and English in Text format
PART C: The Editorials of the original e-Books in English in Audio format
However,
PART B: The graphical results of Machine Learning (ML), Deep Learning (DL) and Natural Language Processing (NLP) algorithms AND the Domain Knowledge Expert (DKE) interpretation of the results in Text format – PART B IS ISSUED AS A STANDALONE VOLUME, named
PART A.1: The eTOCs in Spanish in Audio format AND
PART A.2: The eTOCs in Bi-lingual format: Spanish and English in Text format
PART B:
The graphical results of Medical Text Analysis with Machine Learning (ML), Deep Learning (DL) and Natural Language Processing (NLP) algorithms AND the Domain Knowledge Expert (DKE) interpretation of the results in Text format
In this article, I will list 9 free Harvard courses that you can take to learn data science from scratch. Feel free to skip any of these courses if you already possess knowledge of that subject.
Step 1: Programming
The first step you should take when learning data science is to learn to code. You can choose to do this with your choice of programming language?—?ideally Python or R.
If you’d like to learn R, Harvard offers an introductory R course created specifically for data science learners, called Data Science: R Basics.
This program will take you through R concepts like variables, data types, vector arithmetic, and indexing. You will also learn to wrangle data with libraries like dplyr and create plots to visualize data.
If you prefer Python, you can choose to take CS50’s Introduction to Programming with Python offered for free by Harvard. In this course, you will learn concepts like functions, arguments, variables, data types, conditional statements, loops, objects, methods, and more.
Both programs above are self-paced. However, the Python course is more detailed than the R program, and requires a longer time commitment to complete. Also, the rest of the courses in this roadmap are taught in R, so it might be worth learning R to be able to follow along easily.
Step 2: Data Visualization
Visualization is one of the most powerful techniques with which you can translate your findings in data to another person.
With Harvard’s Data Visualization program, you will learn to build visualizations using the ggplot2 library in R, along with the principles of communicating data-driven insights.
Step 3: Probability
In this course, you will learn essential probability concepts that are fundamental to conducting statistical tests on data. The topics taught include random variables, independence, Monte Carlo simulations, expected values, standard errors, and the Central Limit Theorem.
The concepts above will be introduced with the help of a case study, which means that you will be able to apply everything you learned to an actual real-world dataset.
Step 4: Statistics
After learning probability, you can take this course to learn the fundamentals of statistical inference and modelling.
This program will teach you to define population estimates and margin of errors, introduce you to Bayesian statistics, and provide you with the fundamentals of predictive modeling.
Step 5: Productivity Tools (Optional)
I’ve included this project management course as optional since it isn’t directly related to learning data science. Rather, you will be taught to use Unix/Linux for file management, Github, version control, and creating reports in R.
The ability to do the above will save you a lot of time and help you better manage end-to-end data science projects.
Step 6: Data Pre-Processing
The next course in this list is called Data Wrangling, and will teach you to prepare data and convert it into a format that is easily digestible by machine learning models.
You will learn to import data into R, tidy data, process string data, parse HTML, work with date-time objects, and mine text.
As a data scientist, you often need to extract data that is publicly available on the Internet in the form of a PDF document, HTML webpage, or a Tweet. You will not always be presented with clean, formatted data in a CSV file or Excel sheet.
By the end of this course, you will learn to wrangle and clean data to come up with critical insights from it.
Step 7: Linear Regression
Linear regression is a machine learning technique that is used to model a linear relationship between two or more variables. It can also be used to identify and adjust the effect of confounding variables.
This course will teach you the theory behind linear regression models, how to examine the relationship between two variables, and how confounding variables can be detected and removed before building a machine learning algorithm.
Step 8: Machine Learning
Finally, the course you’ve probably been waiting for! Harvard’s machine learning program will teach you the basics of machine learning, techniques to mitigate overfitting, supervised and unsupervised modelling approaches, and recommendation systems.
Step 9: Capstone Project
After completing all the above courses, you can take Harvard’s data science capstone project, where your skills in data visualization, probability, statistics, data wrangling, data organization, regression, and machine learning will be assessed.
With this final project, you will get the opportunity to put together all the knowledge learnt from the above courses and gain the ability to complete a hands-on data science project from scratch.
Note: All the courses above are available on an online learning platform from edX and can be audited for free. If you want a course certificate, however, you will have to pay for one.
Data powers AI. Good data can mean the difference between an impactful solution or one that never gets off the ground. Re-assess the foundational AI questions to ensure your data is working for, not against, you.
Innovation to Reality
The challenges of implementing AI are many. Avoid the common pitfalls with real-world case studies from leaders who have successfully turned their AI solutions into reality.
Harness What’s Possible at the Edge
With its potential for near instantaneous decision making, pioneers are moving AI to the edge. We examine the pros and cons of moving AI decisions to the edge, with the experts getting it right.
Generative AI Solutions
The use of generative AI to boost human creativity is breaking boundaries in creative areas previously untouched by AI. We explore the intersection of data and algorithms enabling collaborative AI processes to design and create.
Data powers AI. Good data can mean the difference between an impactful solution or one that never gets off the ground. Re-assess the foundational AI questions to ensure your data is working for, not against, you.
Data is the most under-valued and de-glamorized aspect of AI. Learn why shifting the focus from model/algorithm development to quality of the data is the next and most efficient, way to improve the decision-making abilities of AI.
Data labeling is key to determining the success or failure of AI applications. Learn how to implement a data-first approach that can transform AI inference, resulting in better models that make better decisions.
Question the status quo. Build stakeholder trust. These are foundational elements of thought leadership in AI. Explore how organizations can use their data and algorithms in ethical and responsible ways while building bigger and more effective systems.
Haniyeh Mahmoudian
Global AI Ethicist, DataRobot
Mainstage Break (10:35 a.m. – 11:05 a.m.)
Networking and refreshments for our live audience and a selection of curated content for those tuning in virtually.
With its next-generation machine learning models fueling precision medicine, French biotech company, Owkin, captured the attention of the pharma industry. Learn how they did it and get tips to navigate the complex task of scaling your innovation.
Networking and refreshments for our live audience.
Innovation to Reality (11:05 a.m. – 12:30 p.m.)
The challenges of implementing AI are many. Avoid the common pitfalls with real-world case studies from leaders who have successfully turned their AI solutions into reality.
Deploying AI in real-world environments benefits from human input before and during implementation. Get an inside look at how organizations can ensure reliable results with the key questions and competing needs that should be considered when implementing AI solutions.
AI is evolving from the research lab into practical real world applications. Learn what issues should be top of mind for businesses, consumers, and researchers as we take a deep dive into AI solutions that increase modern productivity and accelerate intelligence transformation.
Getting AI to work 80% of the time is relatively straightforward, but trustworthy AI requires deployments that work 100% of the time. Unpack some of the biggest challenges that come up when eliminating the 20% gap.
Bali Raghavan
Head of Engineering, Forward
Lunch and Networking Break (12:30 p.m. – 1:30 p.m.)
Lunch served at the MIT Media Lab and a selection of curated content for those tuning in virtually.
Harness What’s Possible at the Edge (1:30 p.m. – 3:15 p.m.)
With its potential for near instantaneous decision making, pioneers are moving AI to the edge. We examine the pros and cons of moving AI decisions to the edge, with the experts getting it right.
To create sustainable business impact, AI capabilities need to be tailored and optimized to an industry or organization’s specific requirements and infrastructure model. Hear how customers’ challenges across industries can be addressed in any compute environment from the cloud to the edge with end-to-end hardware and software optimization.
Kavitha Prasad
VP & GM, Datacenter, AI and Cloud Execution and Strategy, Intel Corporation
Decision making has moved from the edge to the cloud before settling into a hybrid setup for many AI systems. Through the examination of key use-cases, take a deep dive into understanding the benefits and detractors of operating a machine-learning system at the point of inference.
Enable your organization to transform customer experiences through AI at the edge. Learn about the required technologies, including teachable and self-learning AI, that are needed for a successful shift to the edge, and hear how deploying these technologies at scale can unlock richer, more responsive experiences.
Reimagine AI solutions as a unified system, instead of individual components. Through the lens of autonomous vehicles, discover the pros and cons of using an all-inclusive AI-first approach that includes AI decision-making at the edge and see how this thinking can be applied across industry.
Raquel Urtasun
Founder & CEO, Waabi
Mainstage Break (3:15 p.m. – 3:45 p.m.)
Networking and refreshments for our live audience and a selection of curated content for those tuning in virtually.
Advances in machine learning are enabling artists and creative technologists to think about and use AI in new ways. Discuss the concept of creative AI and look at project examples from London’s art scene that illustrate the various ways creative AI is bridging the gap between the traditional art world and the latest technological innovations.
Luba Elliott
Curator, Producer, and Researcher, Creative AI
Generative AI Solutions (3:45 p.m. – 5:10 p.m.)
The use of generative AI to boost human creativity is breaking boundaries in creative areas previously untouched by AI. We explore the intersection of data and algorithms enabling collaborative AI processes to design and create.
Change the design problem with AI. The creative nature of generative AI enhances design capabilities, finding efficiencies and opportunities that humans alone might not conceive. Explore business applications including project planning, construction, and physical design.
Deep learning is data hungry technology. Manually labelled training data has become cost prohibitive and time-consuming. Get a glimpse at how interactive large-scale synthetic data generation can accelerate the AI revolution, unlocking the potential of data-driven artificial intelligence.
Danny Lange
SVP of Artificial Intelligence, Unity Technologies
Push beyond the typical uses of AI. Explore the nexus of art, technology, and human creativity through the unique innovation of kinetic data sculptures that use machines to give physical context and shape to data to rethink how we engage with the physical world.
Refik Anadol
CEO, RAS Lab; Lecturer, UCLA
Last Call with the Editors (5:10 p.m. – 5:20 p.m.)
Before we wrap day 1, join our last call with all of our editors to get their analysis on the day’s topics, themes, and guests.
Networking Reception (5:20 p.m. – 6:20 p.m.)
WEDNESDAY, MARCH 30
Evolving the Algorithms
What’s Next for Deep Learning
Deep learning algorithms have powered most major AI advances of the last decade. We bring you into the top innovation labs to see how they are advancing their deep learning models to find out just how much more we can get out of these algorithms.
AI in Day-To-Day Business
Many organizations are already using AI internally in their day-to-day operations, in areas like cybersecurity, customer service, finance, and manufacturing. We examine the tools that organizations are using when putting AI to work.
Making AI Work for All
As AI increasingly underpins our lives, businesses, and society, we must ensure that AI must work for everyone – not just those represented in datasets, and not just 80% of the time. Examine the challenges and solutions needed to ensure AI works fairly, for all.
Envisioning the Next AI
Some business problems can’t be solved with current deep learning methods. We look at what’s around the corner at the new approaches and most revolutionary ideas propelling us toward the next stage in AI evolution.
Day 2: Evolving the Algorithms (9:00 a.m. – 5:25 p.m.)
What’s Next for Deep Learning (9:10 a.m. – 10:25 a.m.)
Deep learning algorithms have powered most major AI advances of the last decade. We bring you into the top innovation labs to see how they are advancing their deep learning models to find out just how much more we can get out of these algorithms.
Transformer-based language models are revolutionizing the way neural networks process natural language. This deep dive looks at how organizations can put their data to work using transformer models. We consider the problems that business may face as these massive models mature, including training needs, managing parallel processing at scale, and countering offensive data.
Critical thinking may be one step closer for AI by combining large-scale transformers with smart sampling and filtering. Get an early look at how AlphaCode’s entry into competitive programming may lead to a human-like capacity for AI to write original code that solves unforeseen problems.
As advanced AI systems gain greater capabilities in our search for artificial general intelligence, it’s critical to teach them how to understand human intentions. Look at the latest advancements in AI systems and how to ensure they can be truthful, helpful, and safe.
Mira Murati
SVP, Research, Product, & Partnerships, OpenAI
Mainstage Break (10:25 a.m. – 10:55 a.m.)
Networking and refreshments for our live audience and a selection of curated content for those tuning in virtually.
Good data is the bedrock of a self-service data consumption model, which in turn unlocks insights, analytics, personalization at scale through AI. Yet many organizations face immense challenges setting up a robust data foundation. Dive into a pragmatic perspective on abstracting the complexity and untangling the conflicts in data management for better AI.
Naveen Kamat
Executive Director, Data and AI Services, Kyndryl
AI in Day-To-Day Business (10:55 a.m. – 12:20 p.m.)
Many organizations are already using AI internally in their day-to-day operations, in areas like cybersecurity, customer service, finance, and manufacturing. We examine the tools that organizations are using when putting AI to work.
Effectively operationalized AI/ML can unlock untapped potential in your organization. From enhancing internal processes to managing the customer experience, get the pragmatic advice and takeaways leaders need to better understand their internal data to achieve impactful results.
Use AI to maximize reliability of supply chains. Learn the dos and don’ts to managing key processes within your supply chain, including workforce management, streamlining and simplification, and reaping the full value of your supply chain solutions.
Darcy MacClaren
Senior Vice President, Digital Supply Chain, SAP North America
Machine and reinforcement learning enable Spotify to deliver the right content to the right listener at the right time, allowing for personalized listening experiences that facilitate discovery at a global scale. Through user interactions, algorithms suggest new content and creators that keep customers both happy and engaged with the platform. Dive into the details of making better user recommendations.
Tony Jebara
VP of Engineering and Head of Machine Learning, Spotify
Lunch and Networking Break (12:20 p.m. – 1:15 p.m.)
Lunch served at the MIT Media Lab and a selection of curated content for those tuning in virtually.
Making AI Work for All (1:15 p.m. – 2:35 p.m.)
As AI increasingly underpins our lives, businesses, and society, we must ensure that AI must work for everyone – not just those represented in datasets, and not just 80% of the time. Examine the challenges and solutions needed to ensure AI works fairly, for all.
Walk through the practical steps to map and understand the nuances, outliers, and special cases in datasets. Get tips to ensure ethical and trustworthy approaches to training AI systems that grow in scope and scale within a business.
Lauren Bennett
Group Software Engineering Lead, Spatial Analysis and Data Science, Esri
Get an inside look at the long- and short-term benefits of addressing inequities in AI opportunities, ranging from educating the tech youth of the future to a 10,000-foot view on what it will take to ensure that equity top is of mind within society and business alike.
Public policies can help to make AI more equitable and ethical for all. Examine how policies could impact corporations and what it means for building internal policies, regardless of what government adopts. Identify actionable ideas to best move policies forward for the widest benefit to all.
Nicol Turner Lee
Director, Center for Technology Innovation, Brookings Institution
Mainstage Break (2:35 p.m. – 3:05 p.m.)
Networking and refreshments for our live audience and a selection of curated content for those tuning in virtually.
From the U.S. to China, the global robo-taxi race is gaining traction with consumers and regulators alike. Go behind the scenes with AutoX – a Level 4 driving technology company – and hear how it overcame obstacles while launching the world’s second and China’s first public, fully driverless robo-taxi service.
Jianxiong Xiao
Founder and CEO, AutoX
Envisioning the Next AI (3:05 p.m. – 4:50 p.m.)
Some business problems can’t be solved with current deep learning methods. We look at what’s around the corner at the new approaches and most revolutionary ideas propelling us toward the next stage in AI evolution.
The use of AI in finance is gaining traction as organizations realize the advantages of using algorithms to streamline and improve the accuracy of financial tasks. Step through use cases that examine how AI can be used to minimize financial risk, maximize financial returns, optimize venture capital funding by connecting entrepreneurs to the right investors; and more.
Sameena Shah
Managing Director, J.P. Morgan AI Research, JP Morgan Chase
In a study of simulated robotic evolution, it was observed that more complex environments and evolutionary changes to the robot’s physical form accelerated the growth of robot intelligence. Examine this cutting-edge research and decipher what this early discovery means for the next generation of AI and robotics.
Agrim Gupta
PhD Student, Stanford Vision and Learning Lab, Stanford University
Understanding human thinking and reasoning processes could lead to more general, flexible and human-like artificial intelligence. Take a close look at the research building AI inspired by human common-sense that could create a new generation of tools for complex decision-making.
Zenna Tavares
Research Scientist, Columbia University; Co-Founder, Basis
Look under the hood at this innovative approach to AI learning with multi-agent and human-AI interactions. Discover how bots work together and learn together through personal interactions. Recognize the future implications for AI, plus the benefits and obstacles that may come from this new process.
David Ferrucci was the principal investigator for the team that led IBM Watson to its landmark Jeopardy success, awakening the world to the possibilities of AI. We pull back the curtain on AI for a wide-ranging discussion on explicable models, and the next generation of human and machine collaboration creating AI thought partners with limitless applications.
Medical Startups – Artificial Intelligence (AI) Startups in Healthcare
Reporters: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN and Shraga Rottem, MD, DSc,
The motivation for this post is two fold:
First, we are presenting an application of AI, NLP, DL to our own medical text in the Genomics space. Here we present the first section of Part 1 in the following book. Part 1 has six subsections that yielded 12 plots. The entire Book is represented by 38 x 2 = 76 plots.
Second, we bring to the attention of the e-Reader the list of 276 Medical Startups – Artificial Intelligence (AI) Startups in Healthcare as a hot universe of R&D activity in Human Health.
Third, to highlight one academic center with an AI focus
Dear friends of the ETH AI Center,
We would like to provide you with some exciting updates from the ETH AI Center and its growing community.
As the Covid-19 restrictions in Switzerland have recently been lifted, we would like to hear from you what kind of events you would like to see in 2022! Participate in the survey to suggest event formats and topics that you would enjoy being a part of. We are already excited to learn what we can achieve together this year.
We already have many interesting events coming up, we look forward to seeing you at our main and community events!
LPBI Group is applying AI for Medical Text Analysis with Machine Learning and Natural Language Processing: Statistical and Deep Learning
Our Book
Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology
Medical Text Analysis of this Books shows the following results obtained by Madison Davis by applying Wolfram NLP for Biological Languages on our own Text. See below an Example:
From High-Throughput Assay to Systems Biology: New Tools for Drug Discovery
Curator: Stephen J. Williams, PhD
Marc W. Kirschner*
Department of Systems Biology Harvard Medical School
Boston, Massachusetts 02115
With the new excitement about systems biology, there is understandable interest in a definition. This has proven somewhat difficult. Scientific fields, like species, arise by descent with modification, so in their earliest forms even the founders of great dynasties are only marginally different than their sister fields and species. It is only in retrospect that we can recognize the significant founding events. Before embarking on a definition of systems biology, it may be worth remembering that confusion and controversy surrounded the introduction of the term “molecular biology,” with claims that it hardly differed from biochemistry. Yet in retrospect molecular biology was new and different. It introduced both new subject matter and new technological approaches, in addition to a new style.
As a point of departure for systems biology, consider the quintessential experiment in the founding of molecular biology, the one gene one enzyme hypothesis of Beadle and Tatum. This experiment first connected the genotype directly to the phenotype on a molecular level, although efforts in that direction can certainly be found in the work of Archibald Garrod, Sewell Wright, and others. Here a protein (in this case an enzyme) is seen to be a product of a single gene, and a single function; the completion of a specific step in amino acid biosynthesis is the direct result. It took the next 30 years to fill in the gaps in this process. Yet the one gene one enzyme hypothesis looks very different to us today. What is the function of tubulin, of PI-3 kinase or of rac? Could we accurately predict the phenotype of a nonlethal mutation in these genes in a multicellular organism? Although we can connect structure to the gene, we can no longer infer its larger purpose in the cell or in the organism. There are too many purposes; what the protein does is defined by context. The context also includes a history, either developmental or physiological. Thus the behavior of the Wnt signaling pathway depends on the previous lineage, the “where and when” questions of embryonic development. Similarly the behavior of the immune system depends on previous experience in a variable environment. All of these features stress how inadequate an explanation for function we can achieve solely by trying to identify genes (by annotating them!) and characterizing their transcriptional control circuits.
That we are at a crossroads in how to explore biology is not at all clear to many. Biology is hardly in its dotage; the process of discovery seems to have been perfected, accelerated, and made universally applicable to all fields of biology. With the completion of the human genome and the genomes of other species, we have a glimpse of many more genes than we ever had before to study. We are like naturalists discovering a new continent, enthralled with the diversity itself. But we have also at the same time glimpsed the finiteness of this list of genes, a disturbingly small list. We have seen that the diversity of genes cannot approximate the diversity of functions within an organism. In response, we have argued that combinatorial use of small numbers of components can generate all the diversity that is needed. This has had its recent incarnation in the simplistic view that the rules of cis-regulatory control on DNA can directly lead to an understanding of organisms and their evolution. Yet this assumes that the gene products can be linked together in arbitrary combinations, something that is not assured in chemistry. It also downplays the significant regulatory features that involve interactions between gene products, their localization, binding, posttranslational modification, degradation, etc. The big question to understand in biology is not regulatory linkage but the nature of biological systems that allows them to be linked together in many nonlethal and even useful combinations. More and more we come to realize that understanding the conserved genes and their conserved circuits will require an understanding of their special properties that allow them to function together to generate different phenotypes in different tissues of metazoan organisms. These circuits may have certain robustness, but more important they have adaptability and versatility. The ease of putting conserved processes under regulatory control is an inherent design feature of the processes themselves. Among other things it loads the deck in evolutionary variation and makes it more feasible to generate useful phenotypes upon which selection can act.
Systems biology offers an opportunity to study how the phenotype is generated from the genotype and with it a glimpse of how evolution has crafted the phenotype. One aspect of systems biology is the development of techniques to examine broadly the level of protein, RNA, and DNA on a gene by gene basis and even the posttranslational modification and localization of proteins. In a very short time we have witnessed the development of high-throughput biology, forcing us to consider cellular processes in toto. Even though much of the data is noisy and today partially inconsistent and incomplete, this has been a radical shift in the way we tear apart problems one interaction at a time. When coupled with gene deletions by RNAi and classical methods, and with the use of chemical tools tailored to proteins and protein domains, these high-throughput techniques become still more powerful.
High-throughput biology has opened up another important area of systems biology: it has brought us out into the field again or at least made us aware that there is a world outside our laboratories. Our model systems have been chosen intentionally to be of limited genetic diversity and examined in a highly controlled and reproducible environment. The real world of ecology, evolution, and human disease is a very different place. When genetics separated from the rest of biology in the early part of the 20th century, most geneticists sought to understand heredity and chose to study traits in the organism that could be easily scored and could be used to reveal genetic mechanisms. This was later extended to powerful effect to use genetics to study cell biological and developmental mechanisms. Some geneticists, including a large school in Russia in the early 20th century, continued to study the genetics of natural populations, focusing on traits important for survival. That branch of genetics is coming back strongly with the power of phenotypic assays on the RNA and protein level. As human beings we are most concerned not with using our genetic misfortunes to unravel biology’s complexity (important as that is) but with the role of our genetics in our individual survival. The context for understanding this is still not available, even though the data are now coming in torrents, for many of the genes that will contribute to our survival will have small quantitative effects, partially masked or accentuated by other genetic and environmental conditions. To understand the genetic basis of disease will require not just mapping these genes but an understanding of how the phenotype is created in the first place and the messy interactions between genetic variation and environmental variation.
Extracts and explants are relatively accessible to synthetic manipulation. Next there is the explicit reconstruction of circuits within cells or the deliberate modification of those circuits. This has occurred for a while in biology, but the difference is that now we wish to construct or intervene with the explicit purpose of describing the dynamical features of these synthetic or partially synthetic systems. There are more and more tools to intervene and more and more tools to measure. Although these fall short of total descriptions of cells and organisms, the detailed information will give us a sense of the special life-like processes of circuits, proteins, cells in tissues, and whole organisms in their environment. This meso-scale systems biology will help establish the correspondence between molecules and large-scale physiology.
You are probably running out of patience for some definition of systems biology. In any case, I do not think the explicit definition of systems biology should come from me but should await the words of the first great modern systems biologist. She or he is probably among us now. However, if forced to provide some kind of label for systems biology, I would simply say that systems biology is the study of the behavior of complex biological organization and processes in terms of the molecular constituents. It is built on molecular biology in its special concern for information transfer, on physiology for its special concern with adaptive states of the cell and organism, on developmental biology for the importance of defining a succession of physiological states in that process, and on evolutionary biology and ecology for the appreciation that all aspects of the organism are products of selection, a selection we rarely understand on a molecular level. Systems biology attempts all of this through quantitative measurement, modeling, reconstruction, and theory. Systems biology is not a branch of physics but differs from physics in that the primary task is to understand how biology generates variation. No such imperative to create variation exists in the physical world. It is a new principle that Darwin understood and upon which all of life hinges. That sounds different enough for me to justify a new field and a new name. Furthermore, the success of systems biology is essential if we are to understand life; its success is far from assured—a good field for those seeking risk and adventure.
Biologically active small molecules have a central role in drug development, and as chemical probes and tool compounds to perturb and elucidate biological processes. Small molecules can be rationally designed for a given target, or a library of molecules can be screened against a target or phenotype of interest. Especially in the case of phenotypic screening approaches, a major challenge is to translate the compound-induced phenotype into a well-defined cellular target and mode of action of the hit compound. There is no “one size fits all” approach, and recent years have seen an increase in available target deconvolution strategies, rooted in organic chemistry, proteomics, and genetics. This review provides an overview of advances in target identification and mechanism of action studies, describes the strengths and weaknesses of the different approaches, and illustrates the need for chemical biologists to integrate and expand the existing tools to increase the probability of evolving screen hits to robust chemical probes.
5.1.5. Large-Scale Proteomics
While FITExP is based on protein expression regulation during apoptosis, a study of Ruprecht et al. showed that proteomic changes are induced both by cytotoxic and non-cytotoxic compounds, which can be detected by mass spectrometry to give information on a compound’s mechanism of action. They developed a large-scale proteome-wide mass spectrometry analysis platform for MOA studies, profiling five lung cancer cell lines with over 50 drugs. Aggregation analysis over the different cell lines and the different compounds showed that one-quarter of the drugs changed the abundance of their protein target. This approach allowed target confirmation of molecular degraders such as PROTACs or molecular glues. Finally, this method yielded unexpected off-target mechanisms for the MAP2K1/2 inhibitor PD184352 and the ALK inhibitor ceritinib [97]. While such a mapping approach clearly provides a wealth of information, it might not be easily attainable for groups that are not equipped for high-throughput endeavors.
All-in-all, mass spectrometry methods have gained a lot of traction in recent years and have been successfully applied for target deconvolution and MOA studies of small molecules. As with all high-throughput methods, challenges lie in the accessibility of the instruments (both from a time and cost perspective) and data analysis of complex and extensive data sets.
5.2. Genetic Approaches
Both label-based and mass spectrometry proteomic approaches are based on the physical interaction between a small molecule and a protein target, and focus on the proteome for target deconvolution. It has been long realized that genetics provides an alternative avenue to understand a compound’s action, either through precise modification of protein levels, or by inducing protein mutations. First realized in yeast as a genetically tractable organism over 20 years ago, recent advances in genetic manipulation of mammalian cells have opened up important opportunities for target identification and MOA studies through genetic screening in relevant cell types [98]. Genetic approaches can be roughly divided into two main areas, with the first centering on the identification of mutations that confer compound resistance (Figure 3a), and the second on genome-wide perturbation of gene function and the concomitant changes in sensitivity to the compound (Figure 3b). While both methods can be used to identify or confirm drug targets, the latter category often provides many additional insights in the compound’s mode of action.
Figure 3. Genetic methods for target identification and mode of action studies. Schematic representations of (a) resistance cloning, and (b) chemogenetic interaction screens.
5.2.1. Resistance Cloning
The “gold standard” in drug target confirmation is to identify mutations in the presumed target protein that render it insensitive to drug treatment. Conversely, different groups have sought to use this principle as a target identification method based on the concept that cells grown in the presence of a cytotoxic drug will either die or develop mutations that will make them resistant to the compound. With recent advances in deep sequencing it is now possible to then scan the transcriptome [99] or genome [100] of the cells for resistance-inducing mutations. Genes that are mutated are then hypothesized to encode the protein target. For this approach to be successful, there are two initial requirements: (1) the compound needs to be cytotoxic for resistant clones to arise, and (2) the cell line needs to be genetically unstable for mutations to occur in a reasonable timeframe.
In 2012, the Kapoor group demonstrated in a proof-of-concept study that resistance cloning in mammalian cells, coupled to transcriptome sequencing (RNA-seq), yields the known polo-like kinase 1 (PLK1) target of the small molecule BI 2536. For this, they used the cancer cell line HCT-116, which is deficient in mismatch repair and consequently prone to mutations. They generated and sequenced multiple resistant clones, and clustered the clones based on similarity. PLK1 was the only gene that was mutated in multiple groups. Of note, one of the groups did not contain PLK1 mutations, but rather developed resistance through upregulation of ABCBA1, a drug efflux transporter, which is a general and non-specific resistance mechanism [101]. In a following study, they optimized their pipeline “DrugTargetSeqR”, by counter-screening for these types of multidrug resistance mechanisms so that these clones were excluded from further analysis (Figure 3a). Furthermore, they used CRISPR/Cas9-mediated gene editing to determine which mutations were sufficient to confer drug resistance, and as independent validation of the biochemical relevance of the obtained hits [102].
While HCT-116 cells are a useful model cell line for resistance cloning because of their genomic instability, they may not always be the cell line of choice, depending on the compound and process that is studied. Povedana et al. used CRISPR/Cas9 to engineer mismatch repair deficiencies in Ewing sarcoma cells and small cell lung cancer cells. They found that deletion of MSH2 results in hypermutations in these normally mutationally silent cells, resulting in the formation of resistant clones in the presence of bortezomib, MLN4924, and CD437, which are all cytotoxic compounds [103]. Recently, Neggers et al. reasoned that CRISPR/Cas9-induced non-homologous end-joining repair could be a viable strategy to create a wide variety of functional mutants of essential genes through in-frame mutations. Using a tiled sgRNA library targeting 75 target genes of investigational neoplastic drugs in HAP1 and K562 cells, they generated several KPT-9274 (an anticancer agent with unknown target)-resistant clones, and subsequent deep sequencing showed that the resistant clones were enriched in NAMPT sgRNAs. Direct target engagement was confirmed by co-crystallizing the compound with NAMPT [104]. In addition to these genetic mutation strategies, an alternative method is to grow the cells in the presence of a mutagenic chemical to induce higher mutagenesis rates [105,106].
When there is already a hypothesis on the pathway involved in compound action, the resistance cloning methodology can be extended to non-cytotoxic compounds. Sekine et al. developed a fluorescent reporter model for the integrated stress response, and used this cell line for target deconvolution of a small molecule inhibitor towards this pathway (ISRIB). Reporter cells were chemically mutagenized, and ISRIB-resistant clones were isolated by flow cytometry, yielding clones with various mutations in the delta subunit of guanine nucleotide exchange factor eIF2B [107].
While there are certainly successful examples of resistance cloning yielding a compound’s direct target as discussed above, resistance could also be caused by mutations or copy number alterations in downstream components of a signaling pathway. This is illustrated by clinical examples of acquired resistance to small molecules, nature’s way of “resistance cloning”. For example, resistance mechanisms in Hedgehog pathway-driven cancers towards the Smoothened inhibitor vismodegib include compound-resistant mutations in Smoothened, but also copy number changes in downstream activators SUFU and GLI2 [108]. It is, therefore, essential to conduct follow-up studies to confirm a direct interaction between a compound and the hit protein, as well as a lack of interaction with the mutated protein.
5.2.3. “Chemogenomics”: Examples of Gene-Drug Interaction Screens
When genetic perturbations are combined with small molecule drugs in a chemogenetic interaction screen, the effect of a gene’s perturbation on compound action is studied. Gene perturbation can render the cells resistant to the compound (suppressor interaction), or conversely, result in hypersensitivity and enhanced compound potency (synergistic interaction) [5,117,121]. Typically, cells are treated with the compound at a sublethal dose, to ascertain that both types of interactions can be found in the final dataset, and often it is necessary to use a variety of compound doses (i.e., LD20, LD30, LD50) and timepoints to obtain reliable insights (Figure 3b).
An early example of successful coupling of a phenotypic screen and downstream genetic screening for target identification is the study of Matheny et al. They identified STF-118804 as a compound with antileukemic properties. Treatment of MV411 cells, stably transduced with a high complexity, genome-wide shRNA library, with STF-118804 (4 rounds of increasing concentration) or DMSO control resulted in a marked depletion of cells containing shRNAs against nicotinamide phosphoribosyl transferase (NAMPT) [122].
The Bassik lab subsequently directly compared the performance of shRNA-mediated knockdown versus CRISPR/Cas9-knockout screens for the target elucidation of the antiviral drug GSK983. The data coming out of both screens were complementary, with the shRNA screen resulting in hits leading to the direct compound target and the CRISPR screen giving information on cellular mechanisms of action of the compound. A reason for this is likely the level of protein depletion that is reached by these methods: shRNAs lead to decreased protein levels, which is advantageous when studying essential genes. However, knockdown may not result in a phenotype for non-essential genes, in which case a full CRISPR-mediated knockout is necessary to observe effects [123].
Another NAMPT inhibitor was identified in a CRISPR/Cas9 “haplo-insufficiency (HIP)”-like approach [124]. Haploinsuffiency profiling is a well-established system in yeast which is performed in a ~50% protein background by heterozygous deletions [125]. As there is no control over CRISPR-mediated loss of alleles, compound treatment was performed at several timepoints after addition of the sgRNA library to HCT116 cells stably expressing Cas9, in the hope that editing would be incomplete at early timepoints, resulting in residual protein levels. Indeed, NAMPT was found to be the target of phenotypic hit LB-60-OF61, especially at earlier timepoints, confirming the hypothesis that some level of protein needs to be present to identify a compound’s direct target [124]. This approach was confirmed in another study, thereby showing that direct target identification through CRISPR-knockout screens is indeed possible [126].
An alternative strategy was employed by the Weissman lab, where they combined genome-wide CRISPR-interference and -activation screens to identify the target of the phase 3 drug rigosertib. They focused on hits that had opposite action in both screens, as in sensitizing in one but protective in the other, which were related to microtubule stability. In a next step, they created chemical-genetic profiles of a variety of microtubule destabilizing agents, rationalizing that compounds with the same target will have similar drug-gene interactions. For this, they made a focused library of sgRNAs, based on the most high-ranking hits in the rigosertib genome-wide CRISPRi screen, and compared the focused screen results of the different compounds. The profile for rigosertib clustered well with that of ABT-571, and rigorous target validation studies confirmed rigosertib binding to the colchicine binding site of tubulin—the same site as occupied by ABT-571 [127].
From the above examples, it is clear that genetic screens hold a lot of promise for target identification and MOA studies for small molecules. The CRISPR screening field is rapidly evolving, sgRNA libraries are continuously improving and increasingly commercially available, and new tools for data analysis are being developed [128]. The challenge lies in applying these screens to study compounds that are not cytotoxic, where finding the right dosage regimen will not be trivial.
SYSTEMS BIOLOGY AND CANCER RESEARCH & DRUG DISCOVERY
Integrative Analysis of Next-Generation Sequencing for Next-Generation Cancer Research toward Artificial Intelligence
The rapid improvement of next-generation sequencing (NGS) technologies and their application in large-scale cohorts in cancer research led to common challenges of big data. It opened a new research area incorporating systems biology and machine learning. As large-scale NGS data accumulated, sophisticated data analysis methods became indispensable. In addition, NGS data have been integrated with systems biology to build better predictive models to determine the characteristics of tumors and tumor subtypes. Therefore, various machine learning algorithms were introduced to identify underlying biological mechanisms. In this work, we review novel technologies developed for NGS data analysis, and we describe how these computational methodologies integrate systems biology and omics data. Subsequently, we discuss how deep neural networks outperform other approaches, the potential of graph neural networks (GNN) in systems biology, and the limitations in NGS biomedical research. To reflect on the various challenges and corresponding computational solutions, we will discuss the following three topics: (i) molecular characteristics, (ii) tumor heterogeneity, and (iii) drug discovery. We conclude that machine learning and network-based approaches can add valuable insights and build highly accurate models. However, a well-informed choice of learning algorithm and biological network information is crucial for the success of each specific research question
1. Introduction
The development and widespread use of high-throughput technologies founded the era of big data in biology and medicine. In particular, it led to an accumulation of large-scale data sets that opened a vast amount of possible applications for data-driven methodologies. In cancer, these applications range from fundamental research to clinical applications: molecular characteristics of tumors, tumor heterogeneity, drug discovery and potential treatments strategy. Therefore, data-driven bioinformatics research areas have tailored data mining technologies such as systems biology, machine learning, and deep learning, elaborated in this review paper (see Figure 1 and Figure 2). For example, in systems biology, data-driven approaches are applied to identify vital signaling pathways [1]. This pathway-centric analysis is particularly crucial in cancer research to understand the characteristics and heterogeneity of the tumor and tumor subtypes. Consequently, this high-throughput data-based analysis enables us to explore characteristics of cancers with a systems biology and a systems medicine point of view [2].Combining high-throughput techniques, especially next-generation sequencing (NGS), with appropriate analytical tools has allowed researchers to gain a deeper systematic understanding of cancer at various biological levels, most importantly genomics, transcriptomics, and epigenetics [3,4]. Furthermore, more sophisticated analysis tools based on computational modeling are introduced to decipher underlying molecular mechanisms in various cancer types. The increasing size and complexity of the data required the adaptation of bioinformatics processing pipelines for higher efficiency and sophisticated data mining methodologies, particularly for large-scale, NGS datasets [5]. Nowadays, more and more NGS studies integrate a systems biology approach and combine sequencing data with other types of information, for instance, protein family information, pathway, or protein–protein interaction (PPI) networks, in an integrative analysis. Experimentally validated knowledge in systems biology may enhance analysis models and guides them to uncover novel findings. Such integrated analyses have been useful to extract essential information from high-dimensional NGS data [6,7]. In order to deal with the increasing size and complexity, the application of machine learning, and specifically deep learning methodologies, have become state-of-the-art in NGS data analysis.
Figure 1. Next-generation sequencing data can originate from various experimental and technological conditions. Depending on the purpose of the experiment, one or more of the depicted omics types (Genomics, Transcriptomics, Epigenomics, or Single-Cell Omics) are analyzed. These approaches led to an accumulation of large-scale NGS datasets to solve various challenges of cancer research, molecular characterization, tumor heterogeneity, and drug target discovery. For instance, The Cancer Genome Atlas (TCGA) dataset contains multi-omics data from ten-thousands of patients. This dataset facilitates a variety of cancer researches for decades. Additionally, there are also independent tumor datasets, and, frequently, they are analyzed and compared with the TCGA dataset. As the large scale of omics data accumulated, various machine learning techniques are applied, e.g., graph algorithms and deep neural networks, for dimensionality reduction, clustering, or classification. (Created with BioRender.com.)
Figure 2. (a) A multitude of different types of data is produced by next-generation sequencing, for instance, in the fields of genomics, transcriptomics, and epigenomics. (b) Biological networks for biomarker validation: The in vivo or in vitro experiment results are considered ground truth. Statistical analysis on next-generation sequencing data produces candidate genes. Biological networks can validate these candidate genes and highlight the underlying biological mechanisms (Section 2.1). (c) De novo construction of Biological Networks: Machine learning models that aim to reconstruct biological networks can incorporate prior knowledge from different omics data. Subsequently, the model will predict new unknown interactions based on new omics information (Section 2.2). (d) Network-based machine learning: Machine learning models integrating biological networks as prior knowledge to improve predictive performance when applied to different NGS data (Section 2.3). (Created with BioRender.com).
Therefore, a large number of studies integrate NGS data with machine learning and propose a novel data-driven methodology in systems biology [8]. In particular, many network-based machine learning models have been developed to analyze cancer data and help to understand novel mechanisms in cancer development [9,10]. Moreover, deep neural networks (DNN) applied for large-scale data analysis improved the accuracy of computational models for mutation prediction [11,12], molecular subtyping [13,14], and drug repurposing [15,16].
2. Systems Biology in Cancer Research
Genes and their functions have been classified into gene sets based on experimental data. Our understandings of cancer concentrated into cancer hallmarks that define the characteristics of a tumor. This collective knowledge is used for the functional analysis of unseen data.. Furthermore, the regulatory relationships among genes were investigated, and, based on that, a pathway can be composed. In this manner, the accumulation of public high-throughput sequencing data raised many big-data challenges and opened new opportunities and areas of application for computer science. Two of the most vibrantly evolving areas are systems biology and machine learning which tackle different tasks such as understanding the cancer pathways [9], finding crucial genes in pathways [22,53], or predicting functions of unidentified or understudied genes [54]. Essentially, those models include prior knowledge to develop an analysis and enhance interpretability for high-dimensional data [2]. In addition to understanding cancer pathways with in silico analysis, pathway activity analysis incorporating two different types of data, pathways and omics data, is developed to understand heterogeneous characteristics of the tumor and cancer molecular subtyping. Due to its advantage in interpretability, various pathway-oriented methods are introduced and become a useful tool to understand a complex diseases such as cancer [55,56,57].
In this section, we will discuss how two related research fields, namely, systems biology and machine learning, can be integrated with three different approaches (see Figure 2), namely, biological network analysis for biomarker validation, the use of machine learning with systems biology, and network-based models.
2.1. Biological Network Analysis for Biomarker Validation
The detection of potential biomarkers indicative of specific cancer types or subtypes is a frequent goal of NGS data analysis in cancer research. For instance, a variety of bioinformatics tools and machine learning models aim at identify lists of genes that are significantly altered on a genomic, transcriptomic, or epigenomic level in cancer cells. Typically, statistical and machine learning methods are employed to find an optimal set of biomarkers, such as single nucleotide polymorphisms (SNPs), mutations, or differentially expressed genes crucial in cancer progression. Traditionally, resource-intensive in vitro analysis was required to discover or validate those markers. Therefore, systems biology offers in silico solutions to validate such findings using biological pathways or gene ontology information (Figure 2b) [58]. Subsequently, gene set enrichment analysis (GSEA) [50] or gene set analysis (GSA) [59] can be used to evaluate whether these lists of genes are significantly associated with cancer types and their specific characteristics. GSA, for instance, is available via web services like DAVID [60] and g:Profiler [61]. Moreover, other applications use gene ontology directly [62,63]. In addition to gene-set-based analysis, there are other methods that focuse on the topology of biological networks. These approaches evaluate various network structure parameters and analyze the connectivity of two genes or the size and interconnection of their neighbors [64,65]. According to the underlying idea, the mutated gene will show dysfunction and can affect its neighboring genes. Thus, the goal is to find abnormalities in a specific set of genes linked with an edge in a biological network. For instance, KeyPathwayMiner can extract informative network modules in various omics data [66]. In summary, these approaches aim at predicting the effect of dysfunctional genes among neighbors according to their connectivity or distances from specific genes such as hubs [67,68]. During the past few decades, the focus of cancer systems biology extended towards the analysis of cancer-related pathways since those pathways tend to carry more information than a gene set. Such analysis is called Pathway Enrichment Analysis (PEA) [69,70]. The use of PEA incorporates the topology of biological networks. However, simultaneously, the lack of coverage issue in pathway data needs to be considered. Because pathway data does not cover all known genes yet, an integration analysis on omics data can significantly drop in genes when incorporated with pathways. Genes that can not be mapped to any pathway are called ‘pathway orphan.’ In this manner, Rahmati et al. introduced a possible solution to overcome the ‘pathway orphan’ issue [71]. At the bottom line, regardless of whether researchers consider gene-set or pathway-based enrichment analysis, the performance and accuracy of both methods are highly dependent on the quality of the external gene-set and pathway data [72].
2.2. De Novo Construction of Biological Networks
While the known fraction of existing biological networks barely scratches the surface of the whole system of mechanisms occurring in each organism, machine learning models can improve on known network structures and can guide potential new findings [73,74]. This area of research is called de novo network construction (Figure 2c), and its predictive models can accelerate experimental validation by lowering time costs [75,76]. This interplay between in silico biological networks building and mining contributes to expanding our knowledge in a biological system. For instance, a gene co-expression network helps discover gene modules having similar functions [77]. Because gene co-expression networks are based on expressional changes under specific conditions, commonly, inferring a co-expression network requires many samples. The WGCNA package implements a representative model using weighted correlation for network construction that leads the development of the network biology field [78]. Due to NGS developments, the analysis of gene co-expression networks subsequently moved from microarray-based to RNA-seq based experimental data [79]. However, integration of these two types of data remains tricky. Ballouz et al. compared microarray and NGS-based co-expression networks and found the existence of a bias originating from batch effects between the two technologies [80]. Nevertheless, such approaches are suited to find disease-specific co-expressional gene modules. Thus, various studies based on the TCGA cancer co-expression network discovered characteristics of prognostic genes in the network [81]. Accordingly, a gene co-expression network is a condition-specific network rather than a general network for an organism. Gene regulatory networks can be inferred from the gene co-expression network when various data from different conditions in the same organism are available. Additionally, with various NGS applications, we can obtain multi-modal datasets about regulatory elements and their effects, such as epigenomic mechanisms on transcription and chromatin structure. Consequently, a gene regulatory network can consist of solely protein-coding genes or different regulatory node types such as transcription factors, inhibitors, promoter interactions, DNA methylations, and histone modifications affecting the gene expression system [82,83]. More recently, researchers were able to build networks based on a particular experimental setup. For instance, functional genomics or CRISPR technology enables the high-resolution regulatory networks in an organism [84]. Other than gene co-expression or regulatory networks, drug target, and drug repurposing studies are active research areas focusing on the de novo construction of drug-to-target networks to allow the potential repurposing of drugs [76,85].
2.3. Network Based Machine Learning
A network-based machine learning model directly integrates the insights of biological networks within the algorithm (Figure 2d) to ultimately improve predictive performance concerning cancer subtyping or susceptibility to therapy. Following the establishment of high-quality biological networks based on NGS technologies, these biological networks were suited to be integrated into advanced predictive models. In this manner, Zhang et al., categorized network-based machine learning approaches upon their usage into three groups: (i) model-based integration, (ii) pre-processing integration, and (iii) post-analysis integration [7]. Network-based models map the omics data onto a biological network, and proper algorithms travel the network while considering both values of nodes and edges and network topology. In the pre-processing integration, pathway or other network information is commonly processed based on its topological importance. Meanwhile, in the post-analysis integration, omics data is processed solely before integration with a network. Subsequently, omics data and networks are merged and interpreted. The network-based model has advantages in multi-omics integrative analysis. Due to the different sensitivity and coverage of various omics data types, a multi-omics integrative analysis is challenging. However, focusing on gene-level or protein-level information enables a straightforward integration [86,87]. Consequently, when different machine learning approaches tried to integrate two or more different data types to find novel biological insights, one of the solutions is reducing the search space to gene or protein level and integrated heterogeneous datatypes [25,88].
In summary, using network information opens new possibilities for interpretation. However, as mentioned earlier, several challenges remain, such as the coverage issue. Current databases for biological networks do not cover the entire set of genes, transcripts, and interactions. Therefore, the use of networks can lead to loss of information for gene or transcript orphans. The following section will focus on network-based machine learning models and their application in cancer genomics. We will put network-based machine learning into the perspective of the three main areas of application, namely, molecular characterization, tumor heterogeneity analysis, and cancer drug discovery.
3. Network-Based Learning in Cancer Research
As introduced previously, the integration of machine learning with the insights of biological networks (Figure 2d) ultimately aims at improving predictive performance and interpretability concerning cancer subtyping or treatment susceptibility.
3.1. Molecular Characterization with Network Information
Various network-based algorithms are used in genomics and focus on quantifying the impact of genomic alteration. By employing prior knowledge in biological network algorithms, performance compared to non-network models can be improved. A prominent example is HotNet. The algorithm uses a thermodynamics model on a biological network and identifies driver genes, or prognostic genes, in pan-cancer data [89]. Another study introduced a network-based stratification method to integrate somatic alterations and expression signatures with network information [90]. These approaches use network topology and network-propagation-like algorithms. Network propagation presumes that genomic alterations can affect the function of neighboring genes. Two genes will show an exclusive pattern if two genes complement each other, and the function carried by those two genes is essential to an organism [91]. This unique exclusive pattern among genomic alteration is further investigated in cancer-related pathways. Recently, Ku et al. developed network-centric approaches and tackled robustness issues while studying synthetic lethality [92]. Although synthetic lethality was initially discovered in model organisms of genetics, it helps us to understand cancer-specific mutations and their functions in tumor characteristics [91].
Furthermore, in transcriptome research, network information is used to measure pathway activity and its application in cancer subtyping. For instance, when comparing the data of two or more conditions such as cancer types, GSEA as introduced in Section 2 is a useful approach to get an overview of systematic changes [50]. It is typically used at the beginning of a data evaluation [93]. An experimentally validated gene set can provide information about how different conditions affect molecular systems in an organism. In addition to the gene sets, different approaches integrate complex interaction information into GSEA and build network-based models [70]. In contrast to GSEA, pathway activity analysis considers transcriptome data and other omics data and structural information of a biological network. For example, PARADIGM uses pathway topology and integrates various omics in the analysis to infer a patient-specific status of pathways [94]. A benchmark study with pan-cancer data recently reveals that using network structure can show better performance [57]. In conclusion, while the loss of data is due to the incompleteness of biological networks, their integration improved performance and increased interpretability in many cases.
3.2. Tumor Heterogeneity Study with Network Information
The tumor heterogeneity can originate from two directions, clonal heterogeneity and tumor impurity. Clonal heterogeneity covers genomic alterations within the tumor [95]. While de novo mutations accumulate, the tumor obtains genomic alterations with an exclusive pattern. When these genomic alterations are projected on the pathway, it is possible to observe exclusive relationships among disease-related genes. For instance, the CoMEt and MEMo algorithms examine mutual exclusivity on protein–protein interaction networks [96,97]. Moreover, the relationship between genes can be essential for an organism. Therefore, models analyzing such alterations integrate network-based analysis [98].
In contrast, tumor purity is dependent on the tumor microenvironment, including immune-cell infiltration and stromal cells [99]. In tumor microenvironment studies, network-based models are applied, for instance, to find immune-related gene modules. Although the importance of the interaction between tumors and immune cells is well known, detailed mechanisms are still unclear. Thus, many recent NGS studies employ network-based models to investigate the underlying mechanism in tumor and immune reactions. For example, McGrail et al. identified a relationship between the DNA damage response protein and immune cell infiltration in cancer. The analysis is based on curated interaction pairs in a protein–protein interaction network [100]. Most recently, Darzi et al. discovered a prognostic gene module related to immune cell infiltration by using network-centric approaches [101]. Tu et al. presented a network-centric model for mining subnetworks of genes other than immune cell infiltration by considering tumor purity [102].
3.3. Drug Target Identification with Network Information
In drug target studies, network biology is integrated into pharmacology [103]. For instance, Yamanishi et al. developed novel computational methods to investigate the pharmacological space by integrating a drug-target protein network with genomics and chemical information. The proposed approaches investigated such drug-target network information to identify potential novel drug targets [104]. Since then, the field has continued to develop methods to study drug target and drug response integrating networks with chemical and multi-omic datasets. In a recent survey study by Chen et al., the authors compared 13 computational methods for drug response prediction. It turned out that gene expression profiles are crucial information for drug response prediction [105].
Moreover, drug-target studies are often extended to drug-repurposing studies. In cancer research, drug-repurposing studies aim to find novel interactions between non-cancer drugs and molecular features in cancer. Drug-repurposing (or repositioning) studies apply computational approaches and pathway-based models and aim at discovering potential new cancer drugs with a higher probability than de novo drug design [16,106]. Specifically, drug-repurposing studies can consider various areas of cancer research, such as tumor heterogeneity and synthetic lethality. As an example, Lee et al. found clinically relevant synthetic lethality interactions by integrating multiple screening NGS datasets [107]. This synthetic lethality and related-drug datasets can be integrated for an effective combination of anticancer therapeutic strategy with non-cancer drug repurposing.
4. Deep Learning in Cancer Research
DNN models develop rapidly and become more sophisticated. They have been frequently used in all areas of biomedical research. Initially, its development was facilitated by large-scale imaging and video data. While most data sets in the biomedical field would not typically be considered big data, the rapid data accumulation enabled by NGS made it suitable for the application of DNN models requiring a large amount of training data [108]. For instance, in 2019, Samiei et al. used TCGA-based large-scale cancer data as benchmark datasets for bioinformatics machine learning research such as Image-Net in the computer vision field [109]. Subsequently, large-scale public cancer data sets such as TCGA encouraged the wide usage of DNNs in the cancer domain [110]. Over the last decade, these state-of-the-art machine learning methods have been incorporated in many different biological questions [111].
In addition to public cancer databases such as TCGA, the genetic information of normal tissues is stored in well-curated databases such as GTEx [112] and 1000Genomes [113]. These databases are frequently used as control or baseline training data for deep learning [114]. Moreover, other non-curated large-scale data sources such as GEO (https://www.ncbi.nlm.nih.gov/geo/, accessed on 20 May 2021) can be leveraged to tackle critical aspects in cancer research. They store a large-scale of biological data produced under various experimental setups (Figure 1). Therefore, an integration of GEO data and other data requires careful preprocessing. Overall, an increasing amount of datasets facilitate the development of current deep learning in bioinformatics research [115].
4.1. Challenges for Deep Learning in Cancer Research
Many studies in biology and medicine used NGS and produced large amounts of data during the past few decades, moving the field to the big data era. Nevertheless, researchers still face a lack of data in particular when investigating rare diseases or disease states. Researchers have developed a manifold of potential solutions to overcome this lack of data challenges, such as imputation, augmentation, and transfer learning (Figure 3b). Data imputation aims at handling data sets with missing values [116]. It has been studied on various NGS omics data types to recover missing information [117]. It is known that gene expression levels can be altered by different regulatory elements, such as DNA-binding proteins, epigenomic modifications, and post-transcriptional modifications. Therefore, various models integrating such regulatory schemes have been introduced to impute missing omics data [118,119]. Some DNN-based models aim to predict gene expression changes based on genomics or epigenomics alteration. For instance, TDimpute aims at generating missing RNA-seq data by training a DNN on methylation data. They used TCGA and TARGET (https://ocg.cancer.gov/programs/target/data-matrix, accessed on 20 May 2021) data as proof of concept of the applicability of DNN for data imputation in a multi-omics integration study [120]. Because this integrative model can exploit information in different levels of regulatory mechanisms, it can build a more detailed model and achieve better performance than a model build on a single-omics dataset [117,121]. The generative adversarial network (GAN) is a DNN structure for generating simulated data that is different from the original data but shows the same characteristics [122]. GANs can impute missing omics data from other multi-omics sources. Recently, the GAN algorithm is getting more attention in single-cell transcriptomics because it has been recognized as a complementary technique to overcome the limitation of scRNA-seq [123]. In contrast to data imputation and generation, other machine learning approaches aim to cope with a limited dataset in different ways. Transfer learning or few-shot learning, for instance, aims to reduce the search space with similar but unrelated datasets and guide the model to solve a specific set of problems [124]. These approaches train models with data of similar characteristics and types but different data to the problem set. After pre-training the model, it can be fine-tuned with the dataset of interest [125,126]. Thus, researchers are trying to introduce few-shot learning models and meta-learning approaches to omics and translational medicine. For example, Select-ProtoNet applied the ProtoTypical Network [127] model to TCGA transcriptome data and classified patients into two groups according to their clinical status [128]. AffinityNet predicts kidney and uterus cancer subtypes with gene expression profiles [129].
Figure 3. (a) In various studies, NGS data transformed into different forms. The 2-D transformed form is for the convolution layer. Omics data is transformed into pathway level, GO enrichment score, or Functional spectra. (b) DNN application on different ways to handle lack of data. Imputation for missing data in multi-omics datasets. GAN for data imputation and in silico data simulation. Transfer learning pre-trained the model with other datasets and fine-tune. (c) Various types of information in biology. (d) Graph neural network examples. GCN is applied to aggregate neighbor information. (Created with BioRender.com).
4.2. Molecular Charactization with Network and DNN Model
DNNs have been applied in multiple areas of cancer research. For instance, a DNN model trained on TCGA cancer data can aid molecular characterization by identifying cancer driver genes. At the very early stage, Yuan et al. build DeepGene, a cancer-type classifier. They implemented data sparsity reduction methods and trained the DNN model with somatic point mutations [130]. Lyu et al. [131] and DeepGx [132] embedded a 1-D gene expression profile to a 2-D array by chromosome order to implement the convolution layer (Figure 3a). Other algorithms, such as the deepDriver, use k-nearest neighbors for the convolution layer. A predefined number of neighboring gene mutation profiles was the input for the convolution layer. It employed this convolution layer in a DNN by aggregating mutation information of the k-nearest neighboring genes [11]. Instead of embedding to a 2-D image, DeepCC transformed gene expression data into functional spectra. The resulting model was able to capture molecular characteristics by training cancer subtypes [14].
Another DNN model was trained to infer the origin of tissue from single-nucleotide variant (SNV) information of metastatic tumor. The authors built a model by using the TCGA/ICGC data and analyzed SNV patterns and corresponding pathways to predict the origin of cancer. They discovered that metastatic tumors retained their original cancer’s signature mutation pattern. In this context, their DNN model obtained even better accuracy than a random forest model [133] and, even more important, better accuracy than human pathologists [12].
4.3. Tumor Heterogeneity with Network and DNN Model
As described in Section 4.1, there are several issues because of cancer heterogeneity, e.g., tumor microenvironment. Thus, there are only a few applications of DNN in intratumoral heterogeneity research. For instance, Menden et al. developed ’Scaden’ to deconvolve cell types in bulk-cell sequencing data. ’Scaden’ is a DNN model for the investigation of intratumor heterogeneity. To overcome the lack of training datasets, researchers need to generate in silico simulated bulk-cell sequencing data based on single-cell sequencing data [134]. It is presumed that deconvolving cell types can be achieved by knowing all possible expressional profiles of the cell [36]. However, this information is typically not available. Recently, to tackle this problem, single-cell sequencing-based studies were conducted. Because of technical limitations, we need to handle lots of missing data, noises, and batch effects in single-cell sequencing data [135]. Thus, various machine learning methods were developed to process single-cell sequencing data. They aim at mapping single-cell data onto the latent space. For example, scDeepCluster implemented an autoencoder and trained it on gene-expression levels from single-cell sequencing. During the training phase, the encoder and decoder work as denoiser. At the same time, they can embed high-dimensional gene-expression profiles to lower-dimensional vectors [136]. This autoencoder-based method can produce biologically meaningful feature vectors in various contexts, from tissue cell types [137] to different cancer types [138,139].
4.4. Drug Target Identification with Networks and DNN Models
In addition to NGS datasets, large-scale anticancer drug assays enabled the training train of DNNs. Moreover, non-cancer drug response assay datasets can also be incorporated with cancer genomic data. In cancer research, a multidisciplinary approach was widely applied for repurposing non-oncology drugs to cancer treatment. This drug repurposing is faster than de novo drug discovery. Furthermore, combination therapy with a non-oncology drug can be beneficial to overcome the heterogeneous properties of tumors [85]. The deepDR algorithm integrated ten drug-related networks and trained deep autoencoders. It used a random-walk-based algorithm to represent graph information into feature vectors. This approach integrated network analysis with a DNN model validated with an independent drug-disease dataset [15].
The authors of CDRscan did an integrative analysis of cell-line-based assay datasets and other drug and genomics datasets. It shows that DNN models can enhance the computational model for improved drug sensitivity predictions [140]. Additionally, similar to previous network-based models, the multi-omics application of drug-targeted DNN studies can show higher prediction accuracy than the single-omics method. MOLI integrated genomic data and transcriptomic data to predict the drug responses of TCGA patients [141].
4.5. Graph Neural Network Model
In general, the advantage of using a biological network is that it can produce more comprehensive and interpretable results from high-dimensional omics data. Furthermore, in an integrative multi-omics data analysis, network-based integration can improve interpretability over traditional approaches. Instead of pre-/post-integration of a network, recently developed graph neural networks use biological networks as the base structure for the learning network itself. For instance, various pathways or interactome information can be integrated as a learning structure of a DNN and can be aggregated as heterogeneous information. In a GNN study, a convolution process can be done on the provided network structure of data. Therefore, the convolution on a biological network made it possible for the GNN to focus on the relationship among neighbor genes. In the graph convolution layer, the convolution process integrates information of neighbor genes and learns topological information (Figure 3d). Consequently, this model can aggregate information from far-distant neighbors, and thus can outperform other machine learning models [142].
In the context of the inference problem of gene expression, the main question is whether the gene expression level can be explained by aggregating the neighboring genes. A single gene inference study by Dutil et al. showed that the GNN model outperformed other DNN models [143]. Moreover, in cancer research, such GNN models can identify cancer-related genes with better performance than other network-based models, such as HotNet2 and MutSigCV [144]. A recent GNN study with a multi-omics integrative analysis identified 165 new cancer genes as an interactive partner for known cancer genes [145]. Additionally, in the synthetic lethality area, dual-dropout GNN outperformed previous bioinformatics tools for predicting synthetic lethality in tumors [146]. GNNs were also able to classify cancer subtypes based on pathway activity measures with RNA-seq data. Lee et al. implemented a GNN for cancer subtyping and tested five cancer types. Thus, the informative pathway was selected and used for subtype classification [147]. Furthermore, GNNs are also getting more attention in drug repositioning studies. As described in Section 3.3, drug discovery requires integrating various networks in both chemical and genomic spaces (Figure 3d). Chemical structures, protein structures, pathways, and other multi-omics data were used in drug-target identification and repurposing studies (Figure 3c). Each of the proposed applications has a specialty in the different purposes of drug-related tasks. Sun et al. summarized GNN-based drug discovery studies and categorized them into four classes: molecular property and activity prediction, interaction prediction, synthesis prediction, and de novo drug design. The authors also point out four challenges in the GNN-mediated drug discovery. At first, as we described before, there is a lack of drug-related datasets. Secondly, the current GNN models can not fully represent 3-D structures of chemical molecules and protein structures. The third challenge is integrating heterogeneous network information. Drug discovery usually requires a multi-modal integrative analysis with various networks, and GNNs can improve this integrative analysis. Lastly, although GNNs use graphs, stacked layers still make it hard to interpret the model [148].
4.6. Shortcomings in AI and Revisiting Validity of Biological Networks as Prior Knowledge
The previous sections reviewed a variety of DNN-based approaches that present a good performance on numerous applications. However, it is hardly a panacea for all research questions. In the following, we will discuss potential limitations of the DNN models. In general, DNN models with NGS data have two significant issues: (i) data requirements and (ii) interpretability. Usually, deep learning needs a large proportion of training data for reasonable performance which is more difficult to achieve in biomedical omics data compared to, for instance, image data. Today, there are not many NGS datasets that are well-curated and -annotated for deep learning. This can be an answer to the question of why most DNN studies are in cancer research [110,149]. Moreover, the deep learning models are hard to interpret and are typically considered as black-boxes. Highly stacked layers in the deep learning model make it hard to interpret its decision-making rationale. Although the methodology to understand and interpret deep learning models has been improved, the ambiguity in the DNN models’ decision-making hindered the transition between the deep learning model and translational medicine [149,150].
As described before, biological networks are employed in various computational analyses for cancer research. The studies applying DNNs demonstrated many different approaches to use prior knowledge for systematic analyses. Before discussing GNN application, the validity of biological networks in a DNN model needs to be shown. The LINCS program analyzed data of ’The Connectivity Map (CMap) project’ to understand the regulatory mechanism in gene expression by inferring the whole gene expression profiles from a small set of genes (https://lincsproject.org/, accessed on 20 May 2021) [151,152]. This LINCS program found that the gene expression level is inferrable with only nearly 1000 genes. They called this gene list ’landmark genes’. Subsequently, Chen et al. started with these 978 landmark genes and tried to predict other gene expression levels with DNN models. Integrating public large-scale NGS data showed better performance than the linear regression model. The authors conclude that the performance advantage originates from the DNN’s ability to model non-linear relationships between genes [153].
Following this study, Beltin et al. extensively investigated various biological networks in the same context of the inference of gene expression level. They set up a simplified representation of gene expression status and tried to solve a binary classification task. To show the relevance of a biological network, they compared various gene expression levels inferred from a different set of genes, neighboring genes in PPI, random genes, and all genes. However, in the study incorporating TCGA and GTEx datasets, the random network model outperformed the model build on a known biological network, such as StringDB [154]. While network-based approaches can add valuable insights to analysis, this study shows that it cannot be seen as the panacea, and a careful evaluation is required for each data set and task. In particular, this result may not represent biological complexity because of the oversimplified problem setup, which did not consider the relative gene-expressional changes. Additionally, the incorporated biological networks may not be suitable for inferring gene expression profiles because they consist of expression-regulating interactions, non-expression-regulating interactions, and various in vivo and in vitro interactions.
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Use of Systems Biology in Anti-Microbial Drug Development
Genomics, Computational Biology and Drug Discovery for Mycobacterial Infections: Fighting the Emergence of Resistance. Asma Munir, Sundeep Chaitanya Vedithi, Amanda K. Chaplin and Tom L. Blundell. Front. Genet., 04 September 2020 | https://doi.org/10.3389/fgene.2020.00965
In an earlier review article (Waman et al., 2019), we discussed various computational approaches and experimental strategies for drug target identification and structure-guided drug discovery. In this review we discuss the impact of the era of precision medicine, where the genome sequences of pathogens can give clues about the choice of existing drugs, and repurposing of others. Our focus is directed toward combatting antimicrobial drug resistance with emphasis on tuberculosis and leprosy. We describe structure-guided approaches to understanding the impacts of mutations that give rise to antimycobacterial resistance and the use of this information in the design of new medicines.
Genome Sequences and Proteomic Structural Databases
In recent years, there have been many focused efforts to define the amino-acid sequences of the M. tuberculosis pan-genome and then to define the three-dimensional structures and functional interactions of these gene products. This work has led to essential genes of the bacteria being revealed and to a better understanding of the genetic diversity in different strains that might lead to a selective advantage (Coll et al., 2018). This will help with our understanding of the mode of antibiotic resistance within these strains and aid structure-guided drug discovery. However, only ∼10% of the ∼4128 proteins have structures determined experimentally.
Several databases have been developed to integrate the genomic and/or structural information linked to drug resistance in Mycobacteria (Table 1). These invaluable resources can contribute to better understanding of molecular mechanisms involved in drug resistance and improvement in the selection of potential drug targets.
There is a dearth of information related to structural aspects of proteins from M. leprae and their oligomeric and hetero-oligomeric organization, which has limited the understanding of physiological processes of the bacillus. The structures of only 12 proteins have been solved and deposited in the protein data bank (PDB). However, the high sequence similarity in protein coding genes between M. leprae and M. tuberculosis allows computational methods to be used for comparative modeling of the proteins of M. leprae. Mainly monomeric models using single template modeling have been defined and deposited in the Swiss Model repository (Bienert et al., 2017), in Modbase (Pieper et al., 2014), and in a collection with other infectious disease agents (Sosa et al., 2018). There is a need for multi-template modeling and building homo- and hetero-oligomeric complexes to better understand the interfaces, druggability and impacts of mutations.
We are now exploiting Vivace, a multi-template modeling pipeline developed in our lab for modeling the proteomes of M. tuberculosis (CHOPIN, see above) and M. abscessus [Mabellini Database (Skwark et al., 2019)], to model the proteome of M. leprae. We emphasize the need for understanding the protein interfaces that are critical to function. An example of this is that of the RNA-polymerase holoenzyme complex from M. leprae. We first modeled the structure of this hetero-hexamer complex and later deciphered the binding patterns of rifampin (Vedithi et al., 2018; Figures 1A,B). Rifampin is a known drug to treat tuberculosis and leprosy. Owing to high rifampin resistance in tuberculosis and emerging resistance in leprosy, we used an approach known as “Computational Saturation Mutagenesis”, to identify sites on the protein that are less impacted by mutations. In this study, we were able to understand the association between predicted impacts of mutations on the structure and phenotypic rifampin-resistance outcomes in leprosy.
FIGURE 2
Figure 2.(A) Stability changes predicted by mCSM for systematic mutations in the ß-subunit of RNA polymerase in M. leprae. The maximum destabilizing effect from among all 19 possible mutations at each residue position is considered as a weighting factor for the color map that gradients from red (high destabilizing effects) to white (neutral to stabilizing effects) (Vedithi et al., 2020). (B) One of the known mutations in the ß-subunit of RNA polymerase, the S437H substitution which resulted in a maximum destabilizing effect [-1.701 kcal/mol (mCSM)] among all 19 possibilities this position. In the mutant, histidine (residue in green) forms hydrogen bonds with S434 and Q438, aromatic interactions with F431, and other ring-ring and π interactions with the surrounding residues which can impact the shape of the rifampin binding pocket and rifampin affinity to the ß-subunit [-0.826 log(affinity fold change) (mCSM-lig)]. Orange dotted lines represent weak hydrogen bond interactions. Ring-ring and intergroup interactions are depicted in cyan. Aromatic interactions are represented in sky-blue and carbonyl interactions in pink dotted lines. Green dotted lines represent hydrophobic interactions (Vedithi et al., 2020).
Examples of Understanding and Combatting Resistance
The availability of whole genome sequences in the present era has greatly enhanced the understanding of emergence of drug resistance in infectious diseases like tuberculosis. The data generated by the whole genome sequencing of clinical isolates can be screened for the presence of drug-resistant mutations. A preliminary in silico analysis of mutations can then be used to prioritize experimental work to identify the nature of these mutations.
FIGURE 3
Figure 3.(A) Mechanism of isoniazid activation and INH-NAD adduct formation. (B) Mutations mapped (Munir et al., 2019) on the structure of KatG (PDB ID:1SJ2; Bertrand et al., 2004).
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